Inositol and Berberine Synergistically Reprogram Endocrine and Ovarian Metabolism in Polycystic Ovary Syndrome

Although Myo-Inositol/D-Chiro-Inositol (Ins) and berberine (BBR) have each shown beneficial effects in polycystic ovary syndrome (PCOS), their combined therapeutic potential has not been systematically evaluated. Here, we demonstrate that Ins/BBR exerts superior efficacy compared with single treatments by targeting multiple pathogenic pathways in PCOS. In a DHEA+HFD-induced mouse model, Ins/BBR restored systemic sex steroid balance, normalized LH/FSH ratio, and improved estrous cyclicity. It also reduced ovarian cysts and enhanced fertility, accompanied by partial normalization of steroidogenic enzyme expression. At the cellular level, Ins/BBR alleviated mitochondrial defects and broadly reprogrammed metabolic landscape in granulosa cells, in specific, restoring nucleotide pools and amino acid turnover and preventing abnormal long-chain fatty acid accumulation. Together, these findings provide preclinical evidence that Ins/BBR acts through coordinated endocrine, ovarian and metabolic mechanisms, supporting its promise as a safe and effective therapeutic strategy for PCOS.