Abstract
Diabetes mellitus is associated with an increased risk of several malignancies, driven by shared pathophysiological mechanisms including chronic inflammation, oxidative stress, insulin resistance, and dysregulated growth factor signaling. This study adopts a narrative and mechanistic review design, synthesizing evidence from preclinical and selected clinical studies to examine how marine-derived nutraceutical compounds potentially modulate molecular pathways implicated in diabetes-induced carcinogenesis. The review focuses on key bioactive classes, including marine polysaccharides (e.g., fucoidan and alginate), omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid), polyphenols (fucoxanthin and phlorotannins), and marine peptides. Across experimental models, these compounds have been consistently associated with reduced markers of oxidative stress, suppression of pro-inflammatory mediators (e.g., NF-κB and IL-6), and modulation of insulin-related pathways such as IGF-1/PI3K/Akt and MAPK signaling. Reported effects include reductions in reactive oxygen species levels, downregulation of inflammatory cytokine expression, and improved metabolic biomarkers in in vitro and animal models. However, the evidence remains largely preclinical, with substantial heterogeneity in compound composition, dosing, and bioavailability across studies. Consequently, direct clinical efficacy cannot be inferred. Key limitations include reliance on experimental models, limited quantitative comparability across studies, and translational barriers related to standardization, pharmacokinetics, and long-term safety. Overall, this review provides a mechanistic framework that may inform future translational and clinical investigations, while underscoring the need for rigorously designed human studies.
Introduction
The growing prevalence of diabetes and cancer poses a pressing challenge to public health, as these two conditions are leading causes of morbidity and mortality (1–3). Mounting epidemiological evidence indicates a complex relationship between diabetes and cancer, where individuals with diabetes face an increased risk of developing malignancies such as liver, pancreas, colorectal, and breast cancers (4–6). This connection is underpinned by shared molecular and metabolic pathways, including chronic inflammation, oxidative stress, insulin resistance, and dyslipidemia, which together drive tumorigenesis in diabetic individuals (7,8). These overlapping mechanisms highlight the need for therapeutic strategies that target both conditions simultaneously, reinforcing the importance of a multi-targeted approach to managing their interconnected pathophysiology.
In recent years, research has increasingly shifted towards natural bioactive compounds as potential interventions for complex, multifactorial diseases like diabetes and cancer (Figure 1). Among these, marine nutraceuticals, biologically active compounds derived from marine organisms, have shown considerable promise due to their multifunctional therapeutic properties. Marine-derived compounds such as polysaccharides, polyphenols, omega-3 fatty acids, and peptides have demonstrated the ability to modulate oxidative stress, inflammation, and metabolic dysfunction, offering a novel approach to addressing the shared pathways between diabetes and cancer (9–12). These bioactives provide an opportunity to develop targeted therapies that may regulate insulin sensitivity, improve glycemic control, reduce chronic inflammation, and mitigate cancer progression in diabetic contexts.
Therefore, this study is designed to elucidate the mechanistic pathways through which marine-derived nutraceutical compounds exert biological effects relevant to human health, with a particular focus on antioxidant, anti-inflammatory, and metabolic regulatory processes. Rather than evaluating clinical therapeutic efficacy, the primary objective of this manuscript is to provide a mechanistic and preclinical framework that integrates current experimental evidence on bioactive marine compounds. By synthesizing molecular, cellular, and in vivo findings, this work aims to clarify key biological targets and pathways, thereby supporting future translational and clinical investigations while remaining within the evidentiary boundaries of preclinical data. Throughout this review, the term “diabetes-associated carcinogenesis” is used to describe shared molecular and metabolic pathways linking diabetes and cancer risk, rather than to imply established clinical prevention or therapeutic efficacy.
The structure of this review provides a logical progression of key concepts, beginning with an analysis of the diabetes-cancer connection, followed by an exploration of the bioactive properties of marine nutraceuticals, a review of preclinical and clinical evidence, and a discussion of the challenges and future perspectives in translating these compounds into practical therapeutic strategies.
3. Marine Nutraceuticals and Their Bioactive Potential
The exploration of marine-derived nutraceuticals unveils a promising array of bioactive compounds with significant potential in combating the interconnected challenges of diabetes and cancer. This section delves into the therapeutic roles of various bioactives, including polysaccharides, polyphenols, omega-3 fatty acids, and marine peptides, highlighting their mechanisms in enhancing metabolic health, modulating immune responses, and reducing inflammation and oxidative stress. As the dual burden of these chronic diseases continues to escalate, these bioactive agents could pave the way for innovative multi-targeted therapeutic strategies and preventive measures, offering a sustainable solution to improve human health.
3.1. Major Bioactives
Marine bioactives represent a rich source of compounds with significant potential for addressing the intertwined challenges of diabetes and cancer. From polysaccharides that enhance glycemic control to polyphenols and omega-3 fatty acids that exhibit robust anti-inflammatory and antioxidant effects, these bioactives engage multiple biological pathways critical for metabolic health and tumor suppression. As the narrative unfolds, the diverse roles of these compounds will be explored, setting the stage for understanding their therapeutic efficacy in mitigating the risks associated with these chronic diseases. This exploration serves as a vital component of the broader discourse on integrated strategies for health management in the face of rising global health challenges.
3.1.1. Polysaccharides (Fucoidan, Alginate, Chitosan): Glycemic control, immune modulation
Polysaccharides derived from marine sources, such as fucoidan, alginate, and chitosan, exhibit unique bioactive properties that contribute to their potential therapeutic roles in glycemic control and immune modulation. Fucoidan, a sulfated polysaccharide primarily extracted from brown seaweed, demonstrates significant efficacy in regulating blood glucose levels (86). Its ability to inhibit pivotal enzymes such as α-glucosidase and α-amylase, which facilitate the breakdown of complex carbohydrates into glucose, plays a critical role in mitigating postprandial glucose spikes. By impeding these enzymatic activities, fucoidan not only aids in stabilizing blood sugar levels but also addresses a key metabolic dysfunction associated with diabetes.
In addition to its effects on glycemic regulation, fucoidan exhibits immunemodulating properties that are relevant to diabetes-induced cancer prevention (87). It activates key immune cells, including macrophages and natural killer cells, thereby enhancing immune surveillance and potentially lowering the risk of tumorigenesis in individuals with diabetes. This immune-enhancing action aligns with fucoidan’s capability to suppress pro-inflammatory cytokines such as IL-6 and TNF-α, which are commonly elevated in diabetic conditions and contribute to a chronic inflammatory state. By inhibiting the activation of NF-κB, a central pathway in inflammation and cancer progression, fucoidan not only mitigates inflammation but also disrupts a key mechanistic link between diabetes and cancer. Moreover, through its antiinflammatory actions and its ability to hinder pancreatic lipase activity, fucoidan has been identified as a candidate for addressing metabolic dysfunctions, including obesity, which is closely linked to diabetes and cancer (16). Although these findings highlight the comprehensive bioactivity of fucoidan, variability in its composition due to differences in seaweed species and extraction methods complicates its therapeutic application. Standardized production methods and improved bioavailability are necessary to ensure consistent therapeutic efficacy across diverse clinical populations. Alginate, another marine-derived polysaccharide, contributes to glycemic control through its unique viscosity-enhancing properties. Upon consumption, alginate forms a gel-like matrix in the stomach, which delays gastric emptying and slows nutrient absorption (88). This mechanism not only stabilizes postprandial blood glucose levels but also reduces the overall glycemic load, offering a dietary strategy for managing diabetes. Beyond its impact on glycemia, alginate demonstrates potential in improving lipid profiles by binding to bile acids and cholesterol within the gastrointestinal tract, thereby facilitating their excretion and reducing serum cholesterol and LDL levels (16).
These lipid-lowering effects provide an added benefit in attenuating metabolic dysfunctions that contribute to cancer progression. Alginate has also been studied for its role in countering diet-induced metabolic derangements, with evidence suggesting its efficacy in reducing fat accumulation in the liver and adipose tissues while improving overall metabolic markers (16). Nevertheless, while alginate’s dual role in glycemic and lipid metabolism is well-documented, its effectiveness in human populations requires further exploration. Investigating the long-term impacts of alginate supplementation in clinical trials could elucidate its full therapeutic potential and address gaps in understanding its role in chronic disease management. Chitosan, a bioactive polysaccharide obtained from the exoskeletons of crustaceans, has garnered attention for its immune-modulating properties, particularly its ability to enhance anti-tumor defense mechanisms in diabetes-related carcinogenesis. By stimulating macrophage activation and cytokine production, chitosan enhances the body’s capacity to identify and eliminate pre-cancerous or tumor cells (89). This immune-boosting action is complemented by chitosan’s antiinflammatory properties, which are mediated through the inhibition of proinflammatory cytokines such as IL-6 and TNF-α. The suppression of inflammatory signaling pathways, including NF-κB, positions chitosan as a potential therapeutic agent for addressing the overlapping pathologies of diabetes and cancer (46). Recent studies also highlight the role of chitosan in modulating gut microbiota, particularly its ability to promote the growth of beneficial bacterial species like Lactobacillus and Bifidobacterium. These microbial shifts enhance gut health, reduce systemic inflammation, and potentially mitigate cancer-promoting conditions linked to diabetesrelated dysbiosis (22). However, the variability in the effectiveness of chitosan in influencing gut microbiota composition underscores the need for more targeted research. Future studies should aim to understand the mechanisms underlying chitosan’s interaction with gut microbiota and assess its broader implications for host health.
The multifaceted properties of marine-derived polysaccharides, including their roles in regulating glycemia, modulating the immune system, and reducing inflammation, underscore their potential in addressing the shared pathways of diabetes and cancer. However, significant challenges remain, such as variability in their bioactivity due to environmental factors, differences in extraction techniques, and limited clinical validation. Further research focused on optimizing their formulations and elucidating their molecular mechanisms will be critical for advancing these compounds as viable therapeutic options.
3.1.2. Polyphenols (Fucoxanthin, Phlorotannins): Anti-inflammatory and antioxidant activity.
Polyphenols derived from marine sources, such as fucoxanthin and phlorotannins, are gaining significant attention for their strong anti-inflammatory and antioxidant properties, positioning them as promising candidates for managing the overlapping pathologies of diabetes and cancer. Fucoxanthin, a carotenoid predominantly found in brown algae, demonstrates robust anti-inflammatory activity by suppressing pivotal inflammatory mediators, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (90). This suppression is mediated through the inhibition of nuclear factor kappa B (NF-κB) signaling, a central pathway linked to chronic inflammation and tumor progression in diabetic conditions (21,42). While these findings underscore its therapeutic potential, one critical limitation is the variability across preclinical models, which complicates the extrapolation of results to human health. Further investigations are required to determine whether fucoxanthin can sustain its efficacy in inhibiting NF-κB signaling under diverse physiological conditions and diabetic states. Additionally, its effectiveness in mitigating other inflammation-related pathways needs comprehensive exploration to fully elucidate its capacity to modulate systemic inflammation.
The anti-inflammatory impact of fucoxanthin extends further, including the downregulation of enzymes such as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX), which directly mediate the production of pro-inflammatory compounds. By targeting these enzymes, fucoxanthin disrupts biochemical pathways shared between diabetes and cancer, showcasing multifunctional therapeutic potential (23,44). However, the suppression of COX-2 and LOX activity might interfere with normal physiological repair mechanisms, raising questions about unintended side effects when utilized in long-term therapeutic regimens. Systematic studies evaluating the dose-dependent effects of fucoxanthin on these enzymatic activities are necessary to balance its anti-inflammatory attributes with potential risks.
Experimental studies have further highlighted the role of fucoxanthin in reducing systemic inflammation by inducing macrophage polarization toward the antiinflammatory M2 phenotype. This modulation enhances the secretion of antiinflammatory cytokines, such as interleukin-10 (IL-10), addressing the persistent lowgrade inflammation characteristic of diabetes-related carcinogenesis (16,42). Despite these promising findings, the precise molecular mechanisms underlying macrophage polarization remain poorly defined, limiting the full understanding of how this process contributes to systemic anti-inflammatory effects. Identifying the signaling cascades and transcriptional regulators influenced by fucoxanthin could pave the way for targeted therapeutic approaches, particularly in individuals experiencing severe chronic inflammation.
In addition to its anti-inflammatory properties, fucoxanthin plays a critical role in mitigating oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This activation promotes the increased expression of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase, thereby neutralizing reactive oxygen species (ROS) and safeguarding cellular integrity against damage (23,43). While the activation of Nrf2 presents a promising therapeutic mechanism, sustained activation of this pathway has potential oncogenic implications, as it may inadvertently promote tumor survival by enhancing cellular resistance to oxidative stress. Research focusing on the temporal modulation of Nrf2 activation could aid in minimizing such risks while preserving its protective benefits.
The antioxidant potential of fucoxanthin is further exemplified by its ability to inhibit lipid peroxidation, a process heavily exacerbated in hyperglycemic conditions and associated with DNA damage and cancer progression. Through this inhibition, fucoxanthin demonstrates its capacity to mitigate oxidative damage at the molecular level, disrupting a crucial link between diabetes and cancer (42,91). However, variability exists in the levels of lipid peroxidation inhibition across different experimental settings. Standardized protocols for testing and comparing fucoxanthin’s antioxidative efficacy are needed to enhance translational research and elucidate its therapeutic consistency.
Phlorotannins, another group of marine-derived polyphenols, display potent antioxidant capabilities by scavenging ROS and neutralizing free radicals. These actions are complemented by their ability to upregulate endogenous antioxidant enzymes such as catalase and glutathione reductase, providing comprehensive protection against oxidative stress (23,43). By addressing hyperglycemia-induced ROS generation, phlorotannins interrupt key mechanisms driving DNA damage and mutagenesis, underscoring their relevance in the context of diabetes-induced carcinogenesis (21,27). However, existing studies often focus on isolated biochemical pathways, leaving gaps in understanding how phlorotannins exert their antioxidant effects at the systemic level. Expanding research to include more integrative approaches, such as metabolomic and proteomic analyses, could provide a holistic picture of their therapeutic potential.
Phlorotannins also exhibit anti-inflammatory activity by downregulating proinflammatory cytokines, such as IL-6 and TNF-α, and suppressing the activation of NFκB. Additionally, they inhibit enzymes like COX-2 and LOX, reducing inflammation that contributes to tumor-promoting microenvironments (23,43). This dual antioxidant and anti-inflammatory action positions phlorotannins as a vital component in managing diabetes-related cancers. However, their molecular interactions within the tumor microenvironment are not fully understood, limiting the rational design of therapeutic approaches. Addressing this gap through advanced in vivo studies could unveil new insights into their anti-cancer efficacy.
Beyond their effects on inflammation and oxidative stress, phlorotannins target key signaling pathways implicated in diabetes and cancer. They have been shown to interrupt Toll-like receptor (TLR) signaling, which is associated with insulin resistance and the remodeling of tumor microenvironments (43). This mechanism provides another avenue for addressing the interconnected complications of these diseases but necessitates further validation in clinical settings. Efforts to develop pharmaceutical formulations incorporating phlorotannins face challenges due to their structural instability and potential interactions with other bioactives. Research into stabilizing their bioactive properties during formulation and storage will be critical to their successful application.
Fucoxanthin further impacts cancer progression by inhibiting the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway, which is commonly upregulated in hyperglycemic environments. By targeting this pathway, it reduces cancer cell survival, proliferation, and migration (16,44). However, questions remain regarding the specificity of fucoxanthin’s actions, as off-target effects in normal cells could limit its therapeutic application. Deciphering the structural determinants responsible for its pathway specificity could refine its role in anti-cancer strategies. Phlorotannins similarly modulate cancer-related pathways by inhibiting PI3K/Akt and mammalian target of rapamycin (mTOR) signaling while enhancing pro-apoptotic signaling. These effects are particularly relevant to the dysregulated metabolic environments observed in diabetic patients, where excessive signaling through these pathways often exacerbates tumor progression (23,44). Furthermore, epigenetic modulation by phlorotannins, such as their influence on histone deacetylase (HDAC) activity and DNA methylation, reprograms gene expression related to oxidative stress responses and tumor suppression, adding another layer of therapeutic utility (23). Despite these promising findings, a lack of mechanistic clarity on how these epigenetic changes are induced limits the ability to harness their full potential in clinical interventions.
In summary, fucoxanthin and phlorotannins exemplify the multifaceted capabilities of marine polyphenols in addressing the overlapping mechanisms of diabetes and cancer. Their robust anti-inflammatory, antioxidant, and pathway-modulating properties hold promise for integrative therapeutic approaches. However, challenges associated with variability in efficacy, bioavailability, and mechanistic understanding necessitate further investigation to advance their clinical application.
3.1.3. Omega-3 Fatty Acids (EPA, DHA): Lipid metabolism regulation, apoptosis induction.
Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), hold significant potential in the regulation of lipid metabolism, a crucial factor in diabetes-associated carcinogenesis (92). These essential polyunsaturated fatty acids are noted for their ability to improve lipid profiles by reducing triglyceride levels, lowering low-density lipoprotein (LDL) cholesterol, and increasing high-density lipoprotein (HDL) cholesterol. Such lipid regulatory effects are pivotal, as dyslipidemia, commonly observed in type 2 diabetes mellitus (T2DM), provides abundant lipid substrates that fuel cancer cell proliferation. By mitigating this metabolic dysfunction, EPA and DHA contribute to a decline in cancer risk among individuals with diabetes (23). The therapeutic potential of these compounds is underscored by their ability to correct lipid imbalances; however, variability across clinical and study populations exists, warranting further investigation into optimal dosages and individualized therapeutic strategies.
The role of EPA and DHA in lipid metabolism extends to their activation of key metabolic pathways such as peroxisome proliferator-activated receptors (PPARs). These pathways enhance fatty acid catabolism and reduce lipid accumulation, effectively suppressing cancer cell exploitation of metabolic adaptations, including increased oxidative phosphorylation and fatty acid oxidation (23,27). Additionally, these fatty acids inhibit de novo lipogenesis by downregulating sterol regulatory element-binding proteins (SREBPs), which regulate genes responsible for cholesterol and fatty acid synthesis. This suppression of hepatic lipid production improves metabolic homeostasis while also impeding the development of cancer-promoting lipid-rich environments in diabetic conditions (16). However, while these mechanisms elucidate the biological underpinnings of their efficacy, further exploration is needed to understand how these processes vary under different degrees of metabolic dysfunction, particularly in advanced diabetes stages.
Selective induction of apoptosis in cancer cells by EPA and DHA represents another mechanism by which these fatty acids exert their therapeutic effects. Through the modulation of mitochondrial apoptotic pathways, they upregulate pro-apoptotic proteins such as Bax and caspase-3 while downregulating anti-apoptotic proteins like Bcl-2. This cascade leads to the activation of programmed cell death, specifically targeting tumor cells and sparing normal cells (27). Such selective action is vital in diabetes-related carcinogenesis, where the high glucose environment enhances cancer cell survival. This specificity in targeting diseased cells without damaging healthy ones exemplifies the therapeutic promise of EPA and DHA in reducing diabetes-associated cancer risks. However, a more robust understanding of how these fatty acids interact with cancer cells in hyperglycemic environments is needed to define their precise mechanisms and optimize therapeutic outcomes.
DHA, in particular, has shown a paradoxical ability to exploit cancer cells’ vulnerability to oxidative stress in high-glucose environments. By generating reactive oxygen species (ROS), DHA induces oxidative damage in tumor cells, tipping the already high baseline oxidative stress within these cells to a lethal level. Importantly, adjacent healthy tissues remain unaffected (23). This observation highlights a novel mechanism for targeting cancer cells in diabetic conditions. However, such ROSmediated strategies may carry risks of unintended oxidative damage in off-target tissues if improperly regulated. Future studies should aim to better understand the thresholds for DHA-induced ROS generation to ensure effective targeting of cancer cells while preserving overall tissue integrity.
The ability of EPA and DHA to disrupt cancer survival pathways is central to their anti-tumor potential. They inhibit hyperactivated molecular pathways, such as the phosphatidylinositol-3 kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) pathways, which are instrumental in promoting tumor cell survival, proliferation, and angiogenesis in both diabetes and cancer. By downregulating these pathways, omega3 fatty acids suppress critical processes that sustain tumor growth and resistance to apoptosis in diabetic individuals (16,27). While these findings are promising, additional research into the off-target effects of such pathway inhibition is necessary to avoid unintended disruptions in normal cellular processes. Investigating the structural components of EPA and DHA that confer pathway specificity could refine their role as therapeutic agents.
The anti-inflammatory properties of EPA and DHA are integral to their dual role in managing diabetes and cancer. By reducing pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), these fatty acids attenuate systemic inflammation, which is a primary driver of tumor microenvironment remodeling and insulin resistance in diabetes (23). Chronic inflammation often acts as a catalyst for cancer progression in diabetes by promoting angiogenesis, immune evasion, and tumor-supportive conditions. Omega-3 fatty acids actively counteract these processes through the downregulation of nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2) pathways, paving the way for integrated therapeutic approaches (23,27). While the anti-inflammatory effects of EPA and DHA are well-documented, the interplay between these mechanisms and tumor microenvironment dynamics requires further elucidation, particularly in the context of long-term supplementation.
Another critical mechanism by which omega-3 fatty acids contribute to diabetes and cancer management is their ability to enhance antioxidant defense systems. EPA and DHA reduce cellular oxidative stress by upregulating antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase. This antioxidant action protects cells from the damaging effects of ROS produced under hyperglycemic conditions, a major factor driving DNA mutations and tumorigenesis in diabetes (23). In addition, these fatty acids activate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a central regulator of antioxidant responses. By promoting Nrf2-driven gene expression, EPA and DHA neutralize ROS and reduce the carcinogenic risks associated with oxidative stress in diabetic individuals (16,23). However, caution is warranted, as sustained activation of the Nrf2 pathway may inadvertently enhance cancer cell resilience by promoting oxidative stress resistance. Comprehensive studies are required to optimize the timing and intensity of Nrf2 activation to maximize its benefits while mitigating potential oncogenic risks.
The antioxidative effects of omega-3 fatty acids also extend to the inhibition of lipid peroxidation, a process that is exacerbated by the hyperlipidemic conditions often observed in diabetes. Reduced lipid peroxidation diminishes the formation of mutagenic byproducts, creating a less favorable environment for cancer development.
This multilayered antioxidant capacity underscores the significant role of EPA and DHA in mitigating diabetes-induced carcinogenesis (16,27). Nonetheless, the extent to which these effects translate across diverse clinical settings remains uncertain, highlighting the importance of standardized clinical trials to validate these findings.
Experimental evidence supports the efficacy of dietary omega-3 fatty acids in reducing the risk of diabetes-associated cancers. Preclinical and population-based studies reveal that regular supplementation with EPA and DHA improves lipid metabolism, lowers systemic inflammation, and reduces oxidative stress markers, aligning with findings that demonstrate their ability to modulate interconnected diabetes-cancer pathways (16,27). Epidemiological data further reveal an inverse relationship between dietary omega-3 intake and the incidence of cancers such as colorectal and pancreatic cancers, offering a robust foundation for preventive strategies (23). Despite these promising outcomes, challenges in achieving therapeutic efficacy through omega-3 supplementation persist, primarily due to issues of bioavailability. Improving delivery systems, such as through the development of nanoemulsions, could significantly enhance the therapeutic potential of these fatty acids in preventing and managing diabetes-induced carcinogenesis (16,27).
In conclusion, omega-3 fatty acids exhibit a wide range of beneficial effects on lipid metabolism, inflammation, oxidative stress, and cancer pathway modulation, rendering them valuable candidates for addressing diabetes-associated carcinogenesis. However, further research is crucial to overcome the challenges of bioavailability, understand long-term effects, and refine their application to ensure maximum therapeutic efficacy.
3.1.4. Marine Peptides & Microorganisms: Gut microbiota modulation and anti-cancer properties.
Marine peptides and microorganisms have garnered increasing interest in recent years due to their multifaceted therapeutic potential, particularly in the modulation of gut microbiota and their anti-cancer properties. These bioactive compounds exhibit a range of biological activities with relevance to the management of diabetes and its associated carcinogenic risks, primarily through their ability to influence gut health, systemic inflammation, oxidative stress, and tumor suppression.
Marine peptides extracted from sources such as fish hydrolysates actively contribute to the regulation of the gut microbiota by enhancing the population of beneficial bacterial strains, including Lactobacillus and Bifidobacterium. This improvement in microbial composition is critical for maintaining gut health and reducing systemic inflammation, a key factor linking diabetes to cancer progression (16,46,71). By fostering an environment conducive to the growth of these probiotic species, marine peptides counteract the adverse effects of gut dysbiosis, which is commonly observed in diabetic individuals. However, interindividual variability in response to these bioactives raises questions about how differences in baseline gut microbiota influence their efficacy. Further research using personalized approaches, such as microbiome profiling, is warranted to optimize their therapeutic application.
The ability of marine peptides to promote the production of short-chain fatty acids (SCFAs), including butyrate and propionate, underpins their role in enhancing gut barrier function and reducing permeability. SCFAs strengthen intestinal barrier integrity, thereby decreasing the translocation of lipopolysaccharides (LPS) into systemic circulation. Since LPS is a potent driver of chronic inflammation and insulin resistance, mitigating its translocation can lower diabetes-associated cancer risks (16,46). Nevertheless, the variability in SCFA production across different peptide sources and individuals with varying degrees of gut dysbiosis necessitates standardization in peptide extraction and formulation to ensure consistent therapeutic outcomes.
Marine peptides exert their beneficial effects by restoring microbial diversity and improving overall gut homeostasis. This restoration counters the dysbiotic state prevalent in diabetes, which is characterized by an overabundance of pathogenic bacteria that produce pro-inflammatory metabolites. By reversing this imbalance, marine peptides minimize the production of cancer-promoting compounds and reduce the risk of tumorigenesis associated with diabetes (16,71). However, the long-term impact of marine peptide supplementation on microbial diversity and its downstream effects on systemic health remains underexplored. The incorporation of longitudinal studies could provide insights into the sustainability of these benefits.
In addition to promoting the growth of beneficial bacteria, marine peptides are also effective in suppressing pathogenic bacterial strains. This suppression reduces the harmful effects of dysbiosis, such as the exacerbation of oxidative stress and inflammation, both of which contribute significantly to diabetes-induced carcinogenesis (46,71). The dual ability of marine peptides to bolster good bacteria while inhibiting pathogenic ones highlights their potential as a comprehensive approach for gut health management. However, the mechanisms through which marine peptides selectively act on various microbial species require further clarification to refine their usage in specific pathological conditions.
The antioxidative properties of marine-derived oligopeptides are another critical aspect of their therapeutic potential. By enhancing the activity of enzymatic antioxidants like superoxide dismutase (SOD) and glutathione peroxidase (GPx), these peptides help neutralize reactive oxygen species (ROS) and reduce oxidative stress in hyperglycemic conditions. This action directly prevents oxidative DNA damage, a precursor to carcinogenesis (16,46). While these antioxidative effects are welldocumented in experimental models, challenges remain in translating these findings to clinical settings due to variability in peptide bioavailability and stability.
Marine peptide supplementation also demonstrates anti-inflammatory effects by inhibiting pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). By targeting inflammatory pathways associated with hyperglycemia, these peptides address a central mechanism linking diabetes to cancer (16,46). However, the effectiveness of these peptides in reducing inflammation across different stages of diabetes-associated cancer progression has not been thoroughly investigated. Future studies should focus on identifying the peptide fractions or derivatives most potent in attenuating inflammation.
The dual antioxidant and anti-inflammatory effects of marine bioactives derived from sources such as salmon skin and goby fish have been shown to lower blood glucose levels and improve insulin sensitivity, addressing key parameters in diabetesinduced cancer progression (16,46,71). Despite promising preclinical results, clinical trials evaluating the long-term impacts of these bioactives on glycemic control and cancer prevention remain limited. Ensuring that these interventions are both effective and safe over extended periods will be crucial for their integration into therapeutic protocols.
Marine oligopeptides exhibit antioxidative effects not only by activating enzymatic antioxidants but also by directly neutralizing ROS. This dual action is particularly beneficial in mitigating the oxidative DNA damage and cellular mutations associated with hyperglycemia and carcinogenesis (16,46). Nevertheless, determining the optimal dosage and formulation necessary for achieving these effects remains a challenge, especially given the variability in peptide structure and source.
Certain bioactives from marine organisms, such as soft coral extracts from Sinularia firma and Sinularia erecta, have demonstrated glycation-inhibitory activities. These effects reduce hyperglycemia and improve gut health by limiting the proliferation of pathogenic bacteria that thrive in glycation-promoting environments (16,71). Although these findings highlight the potential of marine bioactives in enhancing metabolic and gut health, further research is needed to assess their efficacy across diverse diabetic populations and cancer types.
Marine peptides have also been shown to influence epigenetic modifications, including the upregulation of genes involved in reducing inflammation and improving insulin sensitivity. For instance, these peptides enhance histone acetylation, which may regulate key inflammatory mediators and reduce diabetes-related tumorigenesis (16,46). While these findings open new avenues for understanding the epigenetic impact of marine bioactives, research elucidating the pathways governing these modifications is still in its infancy and warrants significant attention.
Cyanobacteria-derived compounds exhibit anti-glucosidase and anti-amylase activities, effectively reducing postprandial hyperglycemia. This reduction indirectly affects gut microbial balance by minimizing excess sugar availability, thereby restricting the growth of pathogenic microbes and promoting an anti-carcinogenic environment (16,71). Despite the initial promise of these compounds, variability in their activity across different cyanobacterial strains poses challenges that must be addressed to advance their therapeutic application.
Extracts from Chlorella zofingiensis and Nitzschia laevis, which are rich in astaxanthin, exhibit antiglycative activity that inhibits the formation of advanced glycation end-products (AGEs). This inhibition improves gut integrity and reduces the chronic inflammation associated with diabetes-induced carcinogenesis (16,71). Given the complexity of AGE formation, further studies investigating the molecular pathways targeted by these extracts are essential to establish their broader impact on diabetes and cancer.
Marine peptides further enhance anti-cancer potential by promoting the production of metabolites like butyrate, which induces apoptosis in cancer cells while preserving healthy cells. Butyrate also regulates gene expression related to tumor suppression, offering a dual benefit for mitigating diabetes-related cancer risks (16,17,71). However, variability in butyrate production across populations with differing microbiota compositions emphasizes the need for a personalized approach in peptide supplementation.
Bioactives from cyanobacteria modulate microbial metabolism to produce secondary metabolites with anti-inflammatory and anti-proliferative effects, which reduce cancer-promoting inflammation and inhibit tumor cell growth (16,71). The specificity of these metabolites in targeting inflammatory and cancerous pathways is promising but requires further investigation to confirm their safety and efficacy in complex physiological environments.
Enhanced microbial activity facilitated by marine peptides strengthens systemic immune responses by regulating gut-associated lymphoid tissue (GALT). This regulation activates immune cells such as natural killer (NK) cells and T lymphocytes, which are pivotal in identifying and destroying cancer cells (16,46). While the immunomodulatory abilities of marine peptides hold significant potential, understanding the interplay between gut microbiota and systemic immune responses is critical for optimizing their therapeutic application.
Restoration of gut microbiota through marine-derived bioactives minimizes the production of harmful metabolites that establish a tumor-friendly environment. By addressing metabolic health, these compounds alleviate systemic inflammation and oxidative stress associated with diabetes and cancer (16,71). Despite substantial preclinical evidence, translating these findings into scalable and standardized interventions for human use remains a pressing challenge.
Marine peptides and microorganisms represent a promising frontier in the fight against diabetes-induced carcinogenesis. By modulating the gut microbiota, reducing inflammation, and enhancing systemic health, these bioactives target the interconnected pathways of diabetes and cancer. However, challenges related to variability, formulation, and clinical validation necessitate further research to unlock their full therapeutic potential.
3.2. Mechanistic Actions in Diabetes and Cancer
Delving into the molecular mechanisms that connect diabetes and cancer reveals critical insights into their intertwined pathophysiology. The following sections will illuminate how marine bioactives influence insulin sensitivity, oxidative stress, inflammation, and epigenetic modulation, thereby leveraging multi-targeted actions to address these pressing health challenges. By exploring these mechanistic actions, the discussion underscores the potential of marine-derived compounds in developing effective therapeutic strategies for managing diabetes and mitigating cancer risks. This integrative approach enriches our understanding of the therapeutic landscape,
paving the way for novel interventions.
3.2.1. Regulating Insulin Sensitivity: AMPK activation, GLUT transporter expression
Marine bioactive compounds have emerged as promising agents in enhancing insulin sensitivity, a critical factor in managing diabetes and its associated risk of carcinogenesis. A key mechanism underlying this effect is the activation of AMPactivated protein kinase (AMPK), a crucial regulator of cellular energy homeostasis.
AMPK activation facilitates glucose uptake and utilization, thereby addressing hyperglycemia, a prominent driver of diabetes-induced carcinogenesis (93). For instance, polysaccharides, polyphenols, and omega-3 fatty acids derived from marine sources demonstrate significant potential in directly activating AMPK, which subsequently restores metabolic balance (94). The therapeutic implications of AMPK activation extend beyond glycemic control to antioxidant defenses, emphasizing its role in countering oxidative stress and metabolic dysregulation, which contribute to the tumorigenic environment often observed in diabetic individuals.
One specific example is fucoxanthin, a carotenoid sourced from brown algae, which has been shown to directly activate AMPK, thereby enhancing glucose uptake and reducing hepatic gluconeogenesis (95). This dual effect is particularly relevant, as it addresses both hyperglycemia and insulin resistance. Fucoxanthin’s impact on AMPK activation also supports the enhancement of antioxidant defenses, a necessary intervention given the role of oxidative stress in exacerbating both diabetes and cancer. While preclinical studies provide robust evidence of fucoxanthin’s potential, there remain unanswered questions regarding its long-term effects and pathways in diverse physiological conditions. Further research is required to elucidate whether its benefits can be generalized or if specific diabetic phenotypes are more responsive to its action.
Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have also shown efficacy in improving insulin sensitivity by activating AMPK, particularly in adipose and liver tissues. Through this mechanism, omega-3 fatty acids reduce pro-inflammatory signaling, such as nuclear factor kappa B (NF-κB), which plays a dual role in fostering insulin resistance and supporting tumor progression (16,27). The combination of lipid and glucose metabolism regulation highlights the multifaceted benefits of omega-3 fatty acids. Still, their effects across different stages of diabetes and cancer progression remain underexplored. Questions surrounding optimal dosages and the influence of individual metabolic variability warrant further investigation to inform more tailored therapeutic strategies. Polysaccharides, such as fucoidan derived from brown algae, have demonstrated remarkable capability in ameliorating insulin resistance through AMPK activation and inflammation reduction. Fucoidan has been found to lower blood glucose levels by inhibiting hepatic glucose production, a critical contributor to systemic insulin resistance (96). This dual targeting of metabolic and inflammatory pathways positions fucoidan as a potential therapeutic agent in managing diabetes-induced carcinogenesis. However, despite these promising findings, there is a need for more comprehensive studies to investigate the bioavailability and long-term effects of fucoidan in clinically relevant models.
Marine peptides derived from fish protein hydrolysates represent another class of bioactives with the ability to modulate insulin sensitivity. These peptides interact with insulin receptor substrate-1 (IRS-1) and the PI3K/Akt signaling pathways, thereby reversing insulin resistance and its associated hyperinsulinemia (22,27). This reduction in hyperinsulinemia holds significant implications for cancer prevention, as it disrupts the insulin-like growth factor-1 (IGF-1) axis, a well-documented driver of cancer cell proliferation. However, the specific peptide structures and their interactions within these pathways remain poorly characterized. Elucidating these molecular interactions could pave the way for targeted therapies that address insulin resistance more effectively.
The synergistic effects of marine bioactives, such as fucoxanthin and omega-3 fatty acids, provide a comprehensive approach to mitigating insulin resistance. Experimental research has shown that these compounds improve glucose transport, enhance insulin signaling, and lower inflammatory cytokine levels, underscoring their therapeutic potential in addressing the metabolic disruptions that link diabetes to cancer (16,27). Despite these findings, variability in responses observed across different preclinical models highlights the necessity for standardized protocols to enable consistent translational applications in clinical settings.
Fucoxanthin has also demonstrated the ability to upregulate glucose transporter proteins (GLUTs), particularly GLUT4, in skeletal muscle and adipose tissues. By facilitating GLUT4 translocation to the plasma membrane, fucoxanthin enhances cellular glucose uptake, effectively reducing hyperglycemia and mitigating insulin resistance (16,22). This reduction in circulating glucose disrupts the tumor-promoting environment often observed in hyperglycemic conditions, positioning fucoxanthin as an important agent in diabetes-related cancer prevention. However, further insights are needed into the dose-response relationships and long-term efficacy of fucoxanthin in human populations.
Omega-3 fatty acids such as DHA demonstrate similar effects on GLUT4 translocation, emphasizing their role in enhancing glucose uptake in response to insulin. This mechanism stabilizes blood sugar levels and interrupts pathways contributing to cellular aberrations, including oxidative stress and oncogenic DNA damage (16,27). Despite this promising potential, challenges associated with the bioavailability of DHA highlight the need for innovative delivery systems to optimize its therapeutic application without compromising efficacy.
Polysaccharides such as alginate and fucoidan further exemplify their regulatory effects on GLUT transporters. Fucoidan, in particular, has been identified as a key bioactive in enhancing GLUT4 translocation, thereby improving glucose uptake and minimizing insulin resistance (16,22). This mechanism not only addresses metabolic imbalances but also positions these compounds as preventative agents in cancer development within diabetic contexts. Nonetheless, variability across different experimental models underscores the need for targeted research to bridge preclinical findings with clinical applications.
Marine peptides also show promise in modulating GLUT expression by activating signaling pathways that restore GLUT4 function impaired in insulin-resistant states. This regulation of glucose metabolism provides a critical intervention point for addressing diabetes-induced carcinogenesis (22,27). However, the structural diversity of marine-derived peptides complicates the identification of the most effective candidates, emphasizing the need for focused research to isolate and characterize their active components.
Studies have indicated that dietary supplementation with marine bioactives such as fucoidan and DHA can significantly enhance GLUT4 expression and translocation in preclinical settings. This enhancement not only restores glucose homeostasis but also reduces the pro-inflammatory and metabolic conditions that predispose individuals to cancer (16,27). Translating these findings into human applications requires careful optimization of dosage, formulation, and delivery to ensure both safety and efficacy.
Lastly, omega-3 fatty acids, particularly EPA, highlight a unique ability to improve systemic insulin sensitivity through dual regulation of GLUT transporters and lipid metabolism pathways. This dual action prevents lipid accumulation and metabolic stress, which exacerbate cancer risks in diabetes, thus reinforcing their role as essential components in integrated therapeutic approaches (16,27). Despite these promising mechanisms, further characterization of their molecular interactions is needed to refine their therapeutic applications and minimize off-target effects. In conclusion, marine-derived biomolecules demonstrate extensive potential in regulating insulin sensitivity and mitigating diabetes-related carcinogenesis through mechanisms such as AMPK activation and GLUT translocation. However, their variability in bioactivity and the complexity of their interactions with metabolic pathways necessitate further research to optimize their therapeutic efficacy.
3.2.2. Reducing Oxidative Stress & Inflammation: Nrf2 activation, NF-κB suppression
Marine bioactive compounds, such as fucoidan and polyphenols, have demonstrated significant potential in reducing oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The activation of Nrf2 enhances the expression of critical antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), which are essential for neutralizing reactive oxygen species (ROS) that are excessively generated under hyperglycemic conditions. These elevated ROS levels contribute to cellular damage and a pro-tumorigenic environment, particularly in individuals with diabetes. Such findings underscore the importance of Nrf2 activation in mitigating DNA damage and reducing tumorigenic risks. Despite substantial evidence supporting this mechanism, further investigations are required to ascertain the long-term modulatory effects of fucoidan and polyphenols on antioxidant defenses in diverse diabetic populations, as metabolic and genetic heterogeneity could influence treatment outcomes (16,23).
Fucoidan has demonstrated a dual mechanism in addressing oxidative stress by upregulating Nrf2 while concurrently reducing ROS levels. This integrated action disrupts the cycle of oxidative stress, which not only causes cellular damage but also fosters a tumor-promoting microenvironment. By alleviating oxidative stress, fucoidan plays a crucial role in interrupting key mechanisms that drive cancer progression within diabetic conditions. However, while preclinical studies have highlighted this capability, there is a critical need to assess whether these effects can be consistently reproduced in clinical settings. Variability in its bioavailability and metabolic absorption could influence the extent of its antioxidative impact across patient populations (16,21).
Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), also contribute significantly to reducing oxidative stress by activating the Nrf2 pathway and simultaneously lowering ROS production. Beyond this, omega-3 fatty acids improve mitochondrial function and cellular energy metabolism, enhancing systemic antioxidative capacities. Given the mitochondrial dysfunction observed in diabetes and its role in accelerating oxidative damage, the protective effects of EPA and DHA on mitochondria are particularly noteworthy. Additionally, these benefits align with the broad spectrum of antioxidant activities required to counteract hyperglycemia-induced oxidative stress. Nevertheless, more detailed exploration of how these fatty acids interact with mitochondrial pathways in advanced stages of diabetes is necessary to optimize their therapeutic application (23,43).
Marine polysaccharides such as fucoidan and alginate expand their antioxidative effects by curbing the formation of advanced glycation end-products (AGEs). AGEs are known to exacerbate hyperglycemia-induced oxidative stress and inflammation, bridging these two harmful pathways and amplifying their role in tumorigenesis. By reducing AGE formation, marine polysaccharides disrupt pivotal mechanisms driving oxidative damage and inflammation, making them valuable candidates for addressing diabetes-associated carcinogenesis. However, the variability in AGE formation among individuals with differing glycemic control levels poses a challenge in consistently replicating these effects, emphasizing the need for a stratified approach in their therapeutic application (16).
Experimental findings have revealed that marine peptides derived from fish and mussel hydrolysates activate Nrf2-mediated signaling while simultaneously boosting the activity of endogenous antioxidative enzymes. These findings highlight the multifaceted benefits of marine peptides in enhancing cellular resilience against oxidative stress, especially in hyperglycemic and inflammatory conditions common in diabetes-associated cancers. However, peptide stability and bioavailability remain significant hurdles in their clinical translation. Addressing how these factors can be optimized to ensure consistent antioxidative benefits should be a primary focus of future investigations (43).
Fucoxanthin, a marine polyphenol, has shown the ability to suppress the nuclear factor kappa B (NF-κB) pathway, a critical driver of chronic inflammation. By inhibiting NF-κB translocation to the nucleus, fucoxanthin effectively reduces the synthesis of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factoralpha (TNF-α). This mechanism disrupts the inflammatory pathways that support tumor progression in diabetics, addressing a critical aspect of diabetes-induced carcinogenesis. Despite its potent anti-inflammatory effects, further research should focus on its efficacy across various cancer types and stages associated with diabetes to better define its therapeutic scope (16,23).
The anti-inflammatory actions of fucoidan are similarly critical, given its ability to downregulate NF-κB signaling while promoting anti-inflammatory mediator release. This dual functionality not only reduces systemic inflammation but also disrupts the chronic inflammatory state that supports tumor microenvironment remodeling in diabetes-related cancer. Despite promising preclinical findings, translating these results into consistent clinical efficacy across diverse populations requires addressing issues related to its pharmacokinetics and optimal delivery methods (16,23).
Omega-3 fatty acids further contribute to reducing systemic inflammation through their modulation of NF-κB activity. This suppression results in decreased levels of inflammatory biomarkers, such as C-reactive protein (CRP) and IL-6, which play a role in insulin resistance and tumor progression. The dual benefit of addressing inflammation and improving insulin sensitivity underscores the therapeutic potential of omega-3 fatty acids. Nonetheless, interindividual variability in response to omega3 supplementation highlights the importance of personalized treatment strategies to optimize anti-inflammatory outcomes (16,43).
Marine peptides, particularly those extracted from fish protein hydrolysates, also inhibit the activation of NF-κB by targeting upstream regulators within the inflammatory cascade. These actions significantly reduce the production of proinflammatory cytokines, contributing to the disruption of feedback loops that sustainm chronic inflammation in diabetes. However, addressing the structural diversity of these peptides and identifying the specific bioactive fractions most effective in modulating inflammation remain areas requiring further investigation (43). Marine polysaccharides like fucoidan and alginate exhibit synergistic properties, exerting antioxidative and anti-inflammatory effects by targeting ROS and Nrf2 activation while simultaneously suppressing NF-κB signaling. This dual modulation of oxidative stress and inflammation highlights their comprehensive role in addressing diabetes-associated carcinogenesis. However, refining methods to enhance their bioactivity and stability is essential for their successful integration into therapeutic strategies (16,23).
Evidence from experimental and clinical studies supports the efficacy of marine bioactives, such as fucoxanthin and fucoidan, in simultaneously reducing inflammatory mediators and oxidative stress markers. Targeting Nrf2 and NF-κB pathways, these compounds break the interconnected mechanisms linking hyperglycemia, chronic inflammation, and tumorigenesis. While these findings highlight the therapeutic promise of marine bioactives, variability in their effects across different study designs and populations emphasizes the need for standardized protocols to ensure reproducible outcomes. Optimizing delivery systems to enhance bioavailability remains critical for translating these findings into effective clinical interventions. In conclusion, marine-derived bioactive compounds demonstrate robust antioxidative and anti-inflammatory properties by targeting the Nrf2 and NF-κB pathways. Despite promising evidence, challenges related to bioavailability, population variability, and long-term effects necessitate further exploration to fully harness their therapeutic potential in mitigating diabetes-induced carcinogenesis.
3.2.3. Epigenetic and Gut Microbiome Modulation: SCFA production, miRNA expression
Marine bioactives play a significant role in influencing epigenetic alterations, particularly through their interaction with microRNAs (miRNAs), which regulate critical pathways involved in cancer progression, apoptosis, and cell proliferation. For example, fucoxanthin, a carotenoid derived from marine sources, has been shown to modulate miRNA expression, thereby targeting pathways associated with cancer development. This action provides a novel approach to reversing epigenetic abnormalities that are exacerbated by hyperglycemia and chronic inflammation, both common in diabetes-related conditions (47). However, while the modulatory effects of fucoxanthin on miRNA expression hold potential, research addressing the mechanisms of this regulation in various diabetic and cancerous states remains limited. Expanding investigations into how specific miRNA profiles are affected by fucoxanthin and similar compounds could refine their therapeutic applications and pave the way for personalized interventions.
Certain miRNAs, such as miR-21 and miR-155, are known to be dysregulated in diabetes-related cancers, contributing to tumorigenesis and poor metabolic control. Marine-derived compounds, including polyphenols such as fucoxanthin and phlorotannins, have been reported to normalize these miRNA levels, thereby impairing cancer cell proliferation and improving systemic metabolic health. This dual action underscores the interconnectedness of metabolic and oncogenic pathways influenced by miRNA regulation (23). However, miRNA modulation by marine bioactives remains a developing field, and studies that dissect the precise molecular interactions between these compounds and dysregulated miRNAs are needed. Specifically, the variation in miRNA expression across different cellular environments and cancer types presents a challenge that future research must address to establish the full therapeutic utility of these bioactives.
Evidence indicates that marine polysaccharides, such as fucoidan and alginate, can influence epigenetic landscapes through alterations in DNA methylation and histone modifications. By activating tumor suppressor genes, these compounds could counteract the hyperglycemia-driven silencing of key regulatory pathways in diabetesassociated cancers. This highlights their dual functionality in promoting anticarcinogenic effects while also addressing diabetes-related abnormalities (22). Yet, the complex interactions between polysaccharides and epigenetic regulators require deeper investigation, as the precise molecular pathways through which these modifications occur remain unclear. Moreover, the variation in these epigenetic effects among individuals with different genetic and metabolic profiles adds a layer of complexity to their clinical application, emphasizing the need for targeted studies and standardized models.
Marine bioactives hold significant promise in regulating gut microbiota, with a focus on the production of short-chain fatty acids (SCFAs) such as butyrate. SCFAs play a crucial role in improving gut integrity and reducing systemic inflammation, factors that are often disrupted in the context of diabetes-related carcinogenesis.
Marine peptides, in particular, have been found to promote SCFA production, thereby enhancing gut health and mitigating tumor-promoting pathways. However, while studies have shown the positive effects of SCFAs on systemic inflammation and metabolic disturbances, questions remain regarding the consistency of these effects across different populations and microbiota profiles (22). Future research aimed at understanding how marine peptides interact with the gut microbiota to optimize SCFA production will be pivotal for developing effective therapeutic strategies. Fucoidan and other polysaccharides derived from marine sources are known to selectively stimulate the growth of beneficial microbial species, such as Lactobacillus and Bifidobacterium, which are central to SCFA synthesis. By encouraging the proliferation of these beneficial bacteria, these compounds can mitigate dysbiosis commonly observed in individuals with diabetes, thereby reducing systemic inflammation and fostering a less conducive environment for cancer progression. However, the variability in gut microbial compositions among individuals raises questions about the universality of these effects. Personalized approaches that consider baseline gut microbiota profiles could enhance the efficacy of these interventions, ensuring more consistent therapeutic outcomes (23).
In addition to promoting SCFA production, marine bioactives demonstrate the ability to inhibit pathogenic bacteria that exacerbate inflammation and gut barrier dysfunction. Studies suggest that marine peptides can alter the competitive dynamics within the gut microbiota, favoring the growth of species that contribute to antiinflammatory and anti-cancer effects. While the suppression of pathogenic bacteria by these compounds is promising, the specificity of these interactions and their long-term influence on microbial balance require further exploration. Understanding these dynamics will be key to optimizing marine bioactives as modulators of gut health and systemic inflammation (47).
Besides their effects on gut microbiota, marine bioactives such as fucoidan, phlorotannins, and polyphenols also address the damaging effects of advanced glycation end-products (AGEs) on the gut lining. By counteracting AGE-induced gut permeability, these compounds restore intestinal integrity, which is critical for preventing systemic inflammation and carcinogenesis. Despite these benefits, the molecular pathways by which these bioactives achieve gut barrier restoration remain underexplored. Additional research focusing on their interaction with intestinal epithelial cells and gut-associated lymphoid tissue could provide valuable insights into their mechanisms of action (22).
Marine peptides enhance microbial diversity and activity, thereby improving epithelial integrity while reducing gut-derived inflammation. For example, the fermentation of marine-derived fibers results in bioactive metabolites that target oxidative stress and inflammatory pathways linked to diabetes progression and cancer risk. However, the extent to which these benefits translate into long-term systemic health improvements is not yet well-understood. Longitudinal studies are needed to evaluate the sustainability of these effects and their potential for integration into preventive healthcare strategies (23).
The interplay between gut microbiota, systemic inflammation, and miRNA expression highlights the multifaceted role of marine bioactives. By targeting both microbial composition and miRNA dysregulation, these compounds exhibit a dualaction approach critical to addressing diabetes-associated carcinogenesis. However, clarifying the specific connections between gut microbial changes and epigenetic regulation remains a key area for future research, particularly in understanding how these interactions influence cancer pathways (47).
Marine bioactives exhibit a synergistic influence on gut microbiome health and epigenetic modulation, as exemplified by alginate, which improves microbial profiles while also affecting epigenetic markers in cancer pathways. This dual functionality underscores the integrative potential of marine-derived compounds in addressing the complex molecular underpinnings of diabetes and cancer. Nonetheless, the mechanisms through which these parallel effects occur require further investigation to inform the development of comprehensive therapeutic protocols (22).
The ability of fucoidan to stimulate SCFA production while also modulating miRNA expression highlights its therapeutic versatility in targeting interconnected mechanisms of diabetes and cancer. By addressing hyperglycemia-induced inflammation and oxidative stress at both the gut microbiome and epigenetic levels, fucoidan serves as a potent example of how marine bioactives can provide multitargeted interventions. However, individual variability in response to fucoidan supplementation necessitates a more personalized approach to maximize its therapeutic potential (23).
Marine polyphenols, such as fucoxanthin, further emphasize the cross-talk between epigenetic regulation and gut health. Their dual action in reducing oxidative stress and regulating miRNAs enhances systemic metabolic and immune functions, ultimately addressing the root causes of diabetes-aggravated cancer progression. However, the need to better understand their pharmacokinetics and bioavailability remains a critical step in ensuring their efficacy in clinical populations (47). Future investigations should explore the concurrent use of marine bioactives, such as peptides, polysaccharides, and omega-3 fatty acids, to normalize gut microbiota and epigenetic abnormalities. These multi-component approaches may offer innovative solutions for managing the complex molecular basis of diabetes-induced carcinogenesis. The development of advanced in vivo models and clinical studies will be essential in validating the synergistic effects of these bioactives, particularly in optimizing SCFA-producing bacteria and miRNA regulation. Integrating marine nutraceuticals into dietary regimens provides a sustainable and accessible approach to mitigating the interconnected pathways of diabetes and cancer. Enhanced delivery techniques, such as encapsulated bioactives, could ensure targeted effects on both gut microbiota and systemic circulation. By improving formulation and administration methods, these bioactives could become more effective components of therapeutic strategies aimed at reducing the dual burdens of diabetes and cancer.
3.2.4. Immune System Modulation: Anti-tumor immune response enhancement
Marine-derived bioactives play a pivotal role in modulating the immune system, offering a promising strategy to enhance anti-tumor immune responses in the context of diabetes-associated carcinogenesis. Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have shown efficacy in improving the cytotoxic activity of natural killer (NK) cells and cytotoxic T lymphocytes. These effects are achieved through the downregulation of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin6 (IL-6), while simultaneously upregulating anti-inflammatory cytokines. This dual action helps create an immune-supportive microenvironment capable of mounting more effective tumor-targeting responses. Given the persistent systemic inflammation observed in diabetic individuals, which compromises immune function and facilitates immune evasion by malignant cells, EPA and DHA offer a significant therapeutic advantage by restoring immune surveillance and reducing cancer susceptibility (47,97). However, while these findings are promising, further research is required to determine the optimal dosages and long-term immunomodulatory effects of these fatty acids in diverse diabetic populations.
Dietary supplementation with DHA-rich fish oil has been shown to modulate histone acetylation levels in genes regulating T cell responses, enhancing the immune system’s ability to identify and destroy cancer cells. This epigenetic modulation may be crucial for maintaining effective immune function in individuals with diabetes, where chronic hyperglycemia and inflammation often impair immune defenses. By improving immune cell responsiveness to tumor antigens, DHA underscores the potential of marine-derived bioactives to serve as adjuncts in the prevention of diabetes-induced carcinogenesis (97). Nevertheless, while initial findings highlight the epigenetic influence of DHA on immune genes, mechanistic studies investigating how these histone modifications translate into consistent anti-cancer immune responses are still lacking. Such studies are vital for understanding the broader implications of histone-level changes on immune functionality and cancer prevention.
Fucoidan, a sulfated polysaccharide extracted from marine algae, has demonstrated remarkable potential in enhancing macrophage activity. By promoting the secretion of cytokines such as interleukin-12 (IL-12) and interferon-gamma (IFNγ), fucoidan activates helper T cells, thereby boosting the body’s capacity to mount anti-tumor immune responses while simultaneously mitigating the immunosuppressive environment frequently observed in diabetic conditions (17,46). This immunostimulatory activity positions fucoidan as a dual-action agent capable of addressing both tumorigenesis and diabetes-associated immune dysfunctions. However, the variability in responses to fucoidan across different preclinical models and human studies remains a critical issue. Future research exploring its pharmacokinetics, specifically its bioavailability and absorption in diabetic individuals, is essential to translate its potential into clinical practice effectively.
Marine peptides derived from fish protein hydrolysates suppress regulatory T cells (Tregs), a key immune cell subset that facilitates cancer progression by dampening anti-tumor immune responses. By reducing Treg-mediated immunosuppression, marine peptides promote the activation of effector T cells, which play a critical role in targeting and eliminating tumor cells. This mechanism is particularly relevant in hyperglycemic conditions, which are often characterized by a heightened immunosuppressive state that undermines the immune system’s ability to combat malignancies (46,47). Although this finding highlights the therapeutic promise of marine peptides, the structural diversity and complexity of these peptides present challenges in identifying the most effective candidates. Further studies that dissect the molecular interactions between specific peptides and Treg pathways could pave the way for novel immunotherapeutic interventions targeting diabetes-associated
cancers.
Docosahexaenoic acid (DHA)-rich fish oil contributes further to immune modulation by reducing the immunosuppressive effects of prostaglandin E2 (PGE2), a lipid mediator known to impair immune activity in cancer patients. By lowering PGE2 levels, DHA enables a more robust immune surveillance system capable of recognizing and eliminating precancerous and cancerous cells (97). This mechanism highlights the
potential of DHA as a therapeutic agent to counteract immune dysfunction in diabetesrelated cancer. However, interindividual variability in the anti-inflammatory and immunomodulatory effects of DHA necessitates personalized approaches to optimize its application.
Fucoxanthin, a carotenoid derived from marine algae, enhances the maturation of dendritic cells (DCs). This process is critical for initiating T cell activation against tumor antigens, as mature DCs are more efficient in presenting antigens to T cells. The improved antigen presentation facilitated by fucoxanthin strengthens the immune system’s defense against tumor development, particularly in diabetic patients, where compromised immune responses often accelerate cancer progression (17,47). While these findings underscore the immune supportive benefits of fucoxanthin, additional studies are required to evaluate its efficacy across various cancer types and stages, particularly those closely associated with diabetes.
Spirulina, a marine cyanobacterium, has shown potential in modulating immune responses by reducing serum IgE levels. This reduction suggests that Spirulina may stabilize hypersensitivity and normalize immune function, both of which are critical for cancer prevention in diabetes-related conditions (46,97). By minimizing immune dysfunction and chronic inflammation, Spirulina could serve as a complementary intervention in managing diabetes-induced carcinogenesis. However, the precise molecular pathways through which Spirulina exerts these immunomodulatory effects remain underexplored. Investigating these mechanisms will offer valuable insights into its broader therapeutic applications.
Marine-derived bioactives offer distinct immunomodulatory mechanisms that collectively enhance anti-tumor responses. Despite these promising findings, the challenges of interindividual variability, bioavailability, and long term effects must be addressed to maximize their therapeutic impact.
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Limijadi, E.K.S., Nishani, F., Daliu, P. et al. Marine nutraceuticals and their role in modulating diabetes-induced carcinogenesis. Diabetol Metab Syndr (2026). https://doi.org/10.1186/s13098-026-02113-3
