HMGCS2 attenuates mitochondrial dysregulation and renal fibrosis induced by triclosan.

Renal fibrosis represents a critical pathological mechanism driving the progression of chronic kidney disease toward end-stage renal failure, primarily characterized by the proliferation and deposition of connective tissue within the renal tissue. Triclosan is a widely used synthetic antibacterial agent, and previous studies have demonstrated that TCS exposure interferes with renal fibrosis. However, the pathogenetic mechanism between TCS and renal fibrosis is still unclear. Here, we verified that triclosan exposure led to renal fibrosis, lipid accumulation, and mitochondrial dysregulation in the kidney. Further, we discovered PPARα signals were downregulated in this process, and PPARα agonist partly rescued these effects caused by TCS. We further demonstrated that the ketogenesis defect mediated by Hmgcs2 contributed to renal fibrosis after triclosan exposure. Importantly, Hmgcs2 overexpression could alleviate renal fibrosis and mitochondrial dysregulation after triclosan exposure. Collectively, our findings establish the pivotal role of disrupted PPARα signaling and Hmgcs2 in TCS-induced renal fibrosis, underscoring the critical involvement of mitochondrial dysfunction and impaired ketogenesis. Based on these results, therapeutic regulation of renal ketogenesis could be an effective way to mitigate or even prevent renal fibrosis induced by TCS.