Abstract
Marine ecosystems harbor a remarkable diversity of bioactive compounds with unique chemical structures and potent pharmacological activities. These marine-derived metabolites have gained increasing attention as promising therapeutic agents for metabolic disorders, particularly diabetes and aging-related diseases. This review highlights the emerging roles of marine-sourced Sirtuin 1 (SIRT1) and Nuclear Factor Erythroid 2–Related Factor 2 (NRF2) activators in modulating glucose and lipid metabolism, enhancing antioxidant defense mechanisms, and ameliorating cellular senescence. We summarize the mechanistic pathways by which key marine compounds—such as fucoxanthin, bromophenols, and coral-derived steroids—modulate SIRT1 and NRF2 signaling, potentially providing synergistic effects superior to those of terrestrial or synthetic analogues. The review also addresses the challenges in pharmaceutical formulation and sustainable production, emphasizing the need for advanced biotechnological strategies and innovative delivery systems. While preclinical evidence is compelling, clinical translation remains limited by issues related to bioavailability, safety, and sustainable production. Future research should focus on clinical trials, improved formulations, and sustainable production platforms to unlock the therapeutic potential of marine natural products for diabetes and aging-related metabolic disorders.
Introduction
Marine ecosystems, renowned for their extraordinary biodiversity and chemical complexity, have long fascinated scientists as reservoirs of novel therapeutic agents [1–3]. The escalating global prevalence of chronic metabolic disorders, such as diabetes mellitus and aging-associated metabolic decline, underscores the urgent need for innovative drug candidates [4]. In this context, bioactive compounds derived from marine sources have emerged as promising therapeutic agents due to their capacity to target regulatory pathways fundamental to metabolic health [5, 6].
The escalating global prevalence of chronic metabolic disorders, such as diabetes mellitus and aging-associated metabolic decline, underscores the urgent need for innovative drug candidates [7]. In this context, bioactive compounds derived from marine sources have emerged as promising therapeutic agents due to their capacity to target regulatory pathways fundamental to metabolic health. The sustainable bioproduction of these marine nutraceuticals is crucial, and concepts like “mariculture” and “blue agriculture” offer a primary avenue for their cultivation and large-scale, environmentally responsible supply [8]. By integrating sustainable cultivation methods like seaweed farming and offshore aquaculture, it is possible to ensure a consistent and cost-competitive supply of marine raw materials for drug development, while also providing ecological benefits such as carbon fixation. This approach frames the therapeutic potential of marine compounds within an agricultural context, highlighting the importance of reconciling therapeutic progress with environmental stewardship. This therapeutic potential lies in their ability to modulate key regulatory pathways central to metabolic health.
Among these pathways, Silent Information Regulator 2 Homolog 1 (SIRT1) [9] and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) have attracted considerable scientific interest [10]. SIRT1, a NAD + -dependent deacetylase, plays a pivotal role in the regulation of glucoseand lipid metabolism, insulin sensitivity, and cellular stress responses [11]. Dysregulation of SIRT1 activity is implicated in the pathogenesis of diabetes and agerelated metabolic dysfunction. NRF2, a master transcriptionfactor, orchestrates the expression of antioxidant enzymes, providing cellular protection against oxidative damage and metabolic stress [12, 13]. Targeting SIRT1 and NRF2 thus represents a compelling strategy in the management of metabolic disorders. While the individual roles of SIRT1 in regulating metabolism and NRF2 in orchestrating antioxidant defense are well-established, a comprehensive review that synthesizes the emerging evidence on how marine-derived compounds dually target and exploit the synergistic crosstalk between these two pathways is currently lacking. The novelty of this study lies in its integrative perspective, consolidating fragmented findings to highlight the dual and synergistic modulation of SIRT1 and NRF2 by marine-derived bioactives. The rationality stems from addressing this overlooked intersection, which justifies the research gap by demonstrating how a unified synthesis can reveal broader therapeutic insights for combating multifactorial metabolic disorders. This gap in the literature prevents a cohesive understanding of the multi-targeted therapeutic potential of marine bioactives for complex, multifactorial diseases like diabetes and aging-related metabolic disorders.
Marine natural products offer unique structural features and pharmacological properties that often surpass those of terrestrial-derived compounds [14]. This review addresses the central research question: Can marinederived bioactive compounds that activate SIRT1 and NRF2 serve as effective agents to improve metabolic health? To address this, key chemical classes of marine metabolites with SIRT1 and/or NRF2 activity are identified, along with their pharmaceutical potential and sustainable development as drug candidates for metabolic disorders.
This synthesis is based exclusively on previously published experimental studies; no new primary data are presented. A critical comparison between marine- and terrestrial-derived natural products is provided, together with an overview of the pharmaceutical challenges in drug development and practical considerations such as bioavailability, stability, drug delivery systems, and sustainability in marine drug discovery. Exemplary marine compounds—including fucoxanthin, bromophenols, and napyradiomycins—are highlighted for their documented effects on SIRT1 and NRF2 modulation, improvement of glucose homeostasis, and enhancement of cellular antioxidant defense, though their long-term efficacy and environmental impacts remain to be fully elucidated. The review begins by summarizing the molecular roles of SIRT1 and NRF2 in metabolic regulation and their functional interplay. Recent advances in the discovery and characterization of marine-derived modulators of these pathways are presented, with particular emphasis on structural diversity, biosynthetic origins, and mechanisms of action. The advantages and limitations of marine bioactives are discussed in relation to terrestrial counterparts. Finally, the importance of sustainable sourcing and biotechnological innovation is emphasized to ensure the future viability of marine natural products as therapeuticsfor diabetes and aging-related metabolic disorders.
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Hadinata, E., Harbuwono, D.S., Soegondo, S. et al. Marine nutraceuticals as a source of SIRT1 and NRF2 activators for diabetes and aging-related metabolic disorders. Diabetol Metab Syndr 17, 394 (2025). https://doi.org/10.1186/s13098-025-01981-5
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