Toll-like Receptor 4 Contributes to PCOS-like Metabolic and Reproductive Pathogenesis

Polycystic ovary syndrome (PCOS) is a reproductive disorder with heterogeneous symptoms and severity. Despite extensive research documenting chronic immune dysfunction as a hallmark of PCOS, the specific molecular mechanisms driving immune activation and its connection to the syndromes diverse symptoms remain poorly understood. Emerging evidence suggests that gut-derived bacterial endotoxins, particularly lipopolysaccharide (LPS), may breach the intestinal barriers in PCOS patients and trigger systemic inflammation through Toll-like receptor 4 (TLR4), a pattern recognition receptor of the innate immune system. This study investigated whether TLR4 serves as a critical mechanistic driver of PCOS pathogenesis by examining the effect of genetic TLR4 knockout (TLR4-/-) in a letrozole (LET)-induced mouse model of PCOS. Our results demonstrate that TLR4 deficiency reduces many PCOS-like symptoms, including elevated luteinizing hormone, anovulation, and metabolic dysfunction. TLR4 knockout also preserved estrous cycling and fertility, improved glucose tolerance, maintained gut barrier integrity, and reduced inflammatory markers in LET-treated females. These findings establish TLR4 as a key mediator orchestrating PCOSs multi-system pathology, positioning TLR4 as a critical convergence point rather than affecting individual symptoms in isolation. This novel work reveals that TLR4-mediated inflammation drives multiple PCOS pathologies, opening avenues for targeted anti-inflammatory treatments in women with this disorder. Significance StatementPolycystic ovary syndrome (PCOS) affects up to 15% of reproductive-age women worldwide. This study reveals that TLR4, an innate immune receptor, is key to the pathophysiology of PCOS-like symptoms in female mice. When TLR4 was genetically deleted, mice treated with letrozole to induce PCOS-like symptoms maintained normal weight, glucose regulation, estrous cycling, and fertility. The improvements coincided with preserved gut barrier breakdown and reduced inflammation. These findings identify TLR4 as a key mediator between gut health, immune activation, and PCOS pathophysiology, suggesting that targeting TLR4 could offer new therapeutic approaches for this common but poorly understood syndrome affecting millions of women.