Network Pharmacology and In Vivo Evaluation of Modified Huanglian Wendan Decoction in Polycystic Ovary Syndrome With Insulin Resistance: Association With AGE–RAGE‐Related Signaling

ABSTRACT Modified Huanglian Wendan Decoction (HLWDD) is used for polycystic ovary syndrome with insulin resistance (PCOS‐IR), but its biological basis remains incompletely defined. This study integrated network pharmacology, molecular docking, 100‐ns molecular dynamics (MD), batch‐specific chemical characterization, and in vivo evaluation in a letrozole/high‐fat diet rat model. HPLC fingerprinting showed high batch reproducibility, while UHPLC–HRMS/MS identified 997 candidate library assignments, including 118 higher‐confidence features. Network analysis identified 136 candidate compounds and 532 overlapping PCOS‐related targets, prioritizing AGE–RAGE signaling. Representative docked complexes remained stable during MD and showed negative MM/PBSA binding free energies. In vivo, HLWDD improved estrous‐cycle recovery and ovarian morphology, reduced fasting insulin, HOMA‐IR, reproductive hormones, and inflammatory markers, and modulated ovarian AGE, RAGE, STAT3, and AKT1 expression. High‐dose HLWDD also reduced p‐STAT3/STAT3 and increased p‐AKT/AKT1 relative to the Model group. These findings support an association between HLWDD treatment and AGE–RAGE/STAT3/AKT‐related signaling without establishing causal pathway mediation.