FCGBP links hormonal imbalance and hepatic steatosis in PCOS-NAFLD comorbidity: an integrative bioinformatics and...

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.

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.

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.

This study identifies FCGBP as a potential molecular regulator in PCOS-NAFLD comorbidity and a candidate target for modulating both reproductive and metabolic dysfunctions.