{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:55:06Z","timestamp":1787028906214,"version":"build-2736575974"},"reference-count":87,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Polycystic ovary syndrome (PCOS) is increasingly recognized as a complex, multi-system disorder involving interactions among metabolic dysfunction, chronic low-grade inflammation, and neuroendocrine dysregulation, rather than a condition confined to the ovary. While current management strategies primarily target symptomatic manifestations, such as menstrual irregularity, hyperandrogenism, and insulin resistance, they do not directly address the underlying integrative pathways linking the gut microbiome, cellular energy sensing, and hypothalamic reproductive control. This review proposes a mechanistic framework in which algae-derived bioactives modulate a gut\u2013SIRT1\u2013kisspeptin axis, thereby offering a systems-level perspective on PCOS pathophysiology and intervention. Gut dysbiosis in PCOS contributes to altered bile acid signaling, disrupted microbial metabolite profiles, and increased inflammatory tone, all of which may impair both metabolic and reproductive functions. Concurrently, reduced activity of the NAD+-dependent deacetylase SIRT1 has been documented across ovarian, endometrial, and metabolic tissues, linking energy imbalance to oxidative stress, inflammation, and impaired steroidogenesis. At the neuroendocrine level, dysregulated kisspeptin signaling contributes to abnormal gonadotropin-releasing hormone pulsatility and luteinizing hormone hypersecretion, key features of PCOS. Algae-derived compounds, including polysaccharides, phlorotannins, fucoidan, fucoxanthin, and microalgae bioactives, exhibit prebiotic, anti-inflammatory, and metabolic regulatory properties that intersect with these pathways, particularly through modulation of gut microbiota and activation of AMPK\/SIRT1 signaling. The central proposition of this review is that algae-derived bioactives may act across interconnected biological layers: reshaping gut microbial ecology, restoring SIRT1-mediated metabolic balance, and retuning kisspeptin-driven neuroendocrine activity. While individual components of this axis are supported by substantial evidence, direct experimental validation of the complete pathway remains limited. Therefore, this framework is positioned as a translationally grounded but hypothesis-driven model that integrates currently fragmented findings into a coherent and testable paradigm. Future research should prioritize multi-level experimental and clinical studies that simultaneously assess microbiota composition, metabolic signaling, and reproductive neuroendocrine outcomes to establish the therapeutic potential of algae-based interventions in PCOS.<\/jats:p>","DOI":"10.3390\/md24050185","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T09:12:41Z","timestamp":1779268361000},"page":"185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Algae-Derived Bioactives Reprogram the Gut\u2013SIRT1\u2013Kisspeptin Axis in Polycystic Ovary Syndrome"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6461-5782","authenticated-orcid":false,"given":"Arifa","family":"Mustika","sequence":"first","affiliation":[{"name":"Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Era","family":"Gorica","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences, Albanian University, 1017 Tirana, Albania"},{"name":"Department of Cardiac Surgery, Faculty of Medicine, University Hospital Z\u00fcrich and University of Z\u00fcrich, Wagistrasse 12, 8952 Schlieren, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dante Saksono","family":"Harbuwono","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National Referral Hospital, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eighty Mardiyan","family":"Kurniawati","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0544-2807","authenticated-orcid":false,"given":"Edwin","family":"Hadinata","sequence":"additional","affiliation":[{"name":"School of Medicine, Faculty of Medicine, Universitas Ciputra, Surabaya 60219, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9384-2172","authenticated-orcid":false,"given":"Amal Arifi","family":"Hidayat","sequence":"additional","affiliation":[{"name":"Division of Gastroenterohepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"},{"name":"Medical Research Center of Indonesia, Surabaya 60281, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salmon Charles Pardomuan Tua","family":"Siahaan","sequence":"additional","affiliation":[{"name":"School of Medicine, Faculty of Medicine, Universitas Ciputra, Surabaya 60219, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendy","family":"Hendarto","sequence":"additional","affiliation":[{"name":"School of Medicine, Faculty of Medicine, Universitas Ciputra, Surabaya 60219, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5505-3327","authenticated-orcid":false,"given":"Antonello","family":"Santini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano, 49, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2151-0854","authenticated-orcid":false,"given":"Fahrul","family":"Nurkolis","sequence":"additional","affiliation":[{"name":"Medical Research Center of Indonesia, Surabaya 60281, Indonesia"},{"name":"Institute for Research and Community Service, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta 55281, Indonesia"},{"name":"Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41572-024-00511-3","article-title":"Polycystic Ovary Syndrome","volume":"10","author":"Teede","year":"2024","journal-title":"Nat. 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