Xue Wu, Yonghui Dong, Jia Li, Haiyu Wu, Ji Bian, Caian He, Lin Han, Min Wang
Renal fibrosis, the common pathological endpoint of diverse kidney injuries, drives the progression to end-stage kidney disease. Its rising prevalence, mirroring the global chronic kidney disease burden, starkly contrasts with the unmet need for safe and effective therapies. Fibrogenesis is centrally driven by transforming growth factor-β1 (TGF-β1), which orchestrates epithelial-to-mesenchymal transition and excessive extracellular matrix deposition. While Wnt/β-catenin signalling and mitochondrial dysfunction are key drivers, the specific ligand coupling these processes remains unknown. Here, we identify the dietary flavonoid phloretin as a potent anti-fibrotic agent that selectively downregulates the Wnt ligand, WNT2B. This action curbs aberrant β-catenin signaling and rectifies mitochondrial catastrophe. In TGF-β1-stimulated tubular epithelial cells and folic acid-injured mice, phloretin restores epithelial integrity, suppresses mesenchymal and matrix protein expression, and preserves renal function. Phloretin inhibits WNT2B and rebalances mitochondrial fission/fusion dynamics, reactivating PINK1/Parkin mediated mitophagy, and concurrently attenuates TLR4/MYd88/NLRP3 driven inflammation. Genetic silencing of WNT2B phenocopies the protective effects of phloretin, confirming WNT2B as the critical node coupling Wnt signaling to mitochondrial quality control. Our findings delineate the WNT2B-mitochondrial quality control axis as a tractable therapeutic target and highlight the therapeutic potential of phloretin, a dietary-derived compound, to halt renal fibrosis progression.