Ikrar, Taruna and Siahaan, Salmon Charles and Hendarto, Hendy and Mustika, Arifa and Kurniawati, Eighty Mardiyan and Jatipradresthya, Wiskara and Hadinata, Edwin and Taslim, Nurpudji Astuti and Harbuwono, Dante Saksono and Tjandrawinata, Raymond Rubianto and Nurkolis, Fahrul (2026) 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. Nutrients, 18 (8).

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Abstract

Background: Polycystic ovary syndrome (PCOS) is a complex endocrine�metabolic 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 < 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 �11.4 kcal/mol (CYP17A1) and �10.9 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 < 0.05). Additionally, expression of AKT1 and MAPK1 was significantly restored (p < 0.05). In KGN cells, testosterone levels were significantly decreased while the estradiol levels increased (p < 0.05), accompanied by the downregulation of CYP17A1 and upregulation of CYP19A1 (p < 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. © 2026 by the authors.

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