FCGBP Links Hormonal Imbalance and Hepatic Steatosis in PCOS–NAFLD Comorbidity: An Integrative Bioinformatics and Experimental Study

Background: Polycystic ovary syndrome (PCOS) and nonalcoholic fatty liver disease (NAFLD) are prevalent endocrine-metabolic disorders with a high comorbidity rate. However, their shared molecular mechanisms remain largely unclear. This study aimed to identify and validate key co-expressed genes driving PCOS-NAFLD comorbidity.Methods: Transcriptomic datasets for PCOS (GSE34526) and NAFLD (GSE89632) were analyzed using differential expression combined with three machine learning algorithms (LASSO, Random Forest, and XGBoost). Robustness was assessed using leave-one-out (LOO) resampling and nested cross-validation. Functional enrichment and PPI network analyses identified FCGBP as a key shared gene. A DHEA + high-fat diet–induced rat model was used to simulate key features of PCOS–NAFLD, and DHT+FFA-treated KGN and HepG2 cells were used for in vitro validation, with FCGBP silencing and rescue experiments performed to assess its functional role.Results: FCGBP expression was significantly elevated in both ovarian and hepatic tissues in the rat model (P < 0.01). In KGN cells, FCGBP knockdown restored E2 secretion and upregulated CYP19A1 and HSD17B1 (P < 0.001). In HepG2 cells, FCGBP silencing reduced lipid accumulation and reversed SCD1 upregulation and ATGL downregulation (P < 0.05). These effects were partially reversed by FCGBP re-expression (rescue), further supporting the specificity of its regulatory role. These findings indicate that FCGBP is associated with both hormonal dysregulation and hepatic lipid metabolic abnormalities under hyperandrogenic conditions.Conclusion: This study identifies FCGBP as a potential molecular regulator in PCOS–NAFLD comorbidity and a candidate target for modulating both reproductive and metabolic dysfunctions.