{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:20:35Z","timestamp":1784694035977,"version":"3.55.0"},"reference-count":29,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Polycystic ovary syndrome (PCOS) is a complex endocrine\u2013metabolic disorder characterized by interconnected dysregulation of steroidogenesis and insulin signaling. Multi-target therapeutic strategies are increasingly needed to address its heterogeneous pathophysiology. Methods: An integrative approach combining transcriptomic analysis of GSE137684, including stratification of normoandrogenic and hyperandrogenic PCOS subtypes to capture androgen-related heterogeneity, network pharmacology, molecular docking, and in vitro validation was employed. Principal component analysis (PCA), differential expression analysis, and enrichment analyses were used to identify candidate genes and pathways. Molecular docking evaluated interactions between phytochemicals from Cinnamomum burmannii and Myristica fragrans and key PCOS targets. Functional validation was performed in insulin-resistant 3T3-L1 adipocytes and DHEA-induced KGN cells, assessing cell viability, lipid accumulation, glucose uptake, gene expression, and hormone levels. Results: PCA revealed partial separation between PCOS and the control samples, with PC1 and PC2 explaining 44.8% and 12.5% of variance, respectively. No genes remained significant after multiple testing correction; however, nominally significant candidates (p &lt; 0.01) highlighted pathways related to steroidogenesis and metabolic regulation. Network analysis identified key hub genes including CYP17A1, CYP19A1, AKT1, ESR1, and MAPK1. Molecular docking demonstrated strong binding affinities, with top compounds showing binding energies up to \u221211.4 kcal\/mol (CYP17A1) and \u221210.9 kcal\/mol (AKT1). In vitro, cell viability remained above 80% across all tested concentrations, indicating low cytotoxicity. Treatment significantly reduced lipid accumulation and enhanced glucose uptake in insulin-resistant 3T3-L1 cells (p &lt; 0.05). Additionally, expression of AKT1 and MAPK1 was significantly restored (p &lt; 0.05). In KGN cells, testosterone levels were significantly decreased while the estradiol levels increased (p &lt; 0.05), accompanied by the downregulation of CYP17A1 and upregulation of CYP19A1 (p &lt; 0.05). The combination treatment exhibited more consistent effects across metabolic and hormonal endpoints. Conclusions:Cinnamomum burmannii and Myristica fragrans exert multi-target effects on metabolic and steroidogenic pathways relevant to PCOS. This integrative study demonstrates that transcriptomics-guided network pharmacology combined with experimental validation can identify synergistic phytotherapeutic strategies for complex endocrine disorders.<\/jats:p>","DOI":"10.3390\/nu18081305","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T11:42:45Z","timestamp":1776771765000},"page":"1305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi-Target Modulation of Metabolic and Steroidogenic Pathways by Cinnamomum burmannii and Myristica fragrans in Polycystic Ovary Syndrome: An Integrative Transcriptomics, Metabolomic, Pharmacoinformatics and Experimental Validation"],"prefix":"10.3390","volume":"18","author":[{"given":"Taruna","family":"Ikrar","sequence":"first","affiliation":[{"name":"The Indonesian Food and Drug Authority (BPOM), Jakarta 10560, Indonesia"},{"name":"Universiti Teknologi Malaysia (UTM) Kuala Lumpur, Jalan Sultan Yahya Petra, Kuala Lumpur 54100, Wilayah Persekutuan Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salmon Charles","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\/0000-0001-6461-5782","authenticated-orcid":false,"given":"Arifa","family":"Mustika","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, 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 60131, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiskara","family":"Jatipradresthya","sequence":"additional","affiliation":[{"name":"Center for Health Policy and Management, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55284, 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\/0000-0003-1349-5367","authenticated-orcid":false,"given":"Nurpudji Astuti","family":"Taslim","sequence":"additional","affiliation":[{"name":"Division of Clinical Nutrition, Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar 90245, Indonesia"}],"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":"Raymond Rubianto","family":"Tjandrawinata","sequence":"additional","affiliation":[{"name":"Center for Pharmaceutical and Nutraceutical Research and Policy, School of Bioscience, Technology, and Innovation, Atma Jaya Catholic University of Indonesia, Jakarta 12930, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2151-0854","authenticated-orcid":false,"given":"Fahrul","family":"Nurkolis","sequence":"additional","affiliation":[{"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 60131, Indonesia"},{"name":"Medical Research Center of Indonesia, Surabaya 60281, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,21]]},"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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