Increased WNT10B/FOXO6 signaling promotes cell fate transition in renal tubular cells to aggravate renal inflammation and fibrosis

Abnormal cell fate transition determines cell instability, which can contribute to disease development. In chronic kidney disease, many renal tubular cells exhibit senescent phenotypes. The fundamental mechanisms of this fate transition remain undetermined. Here we discover that WNT10B, a ligand of the Wnt family, accelerates CKD progression through tubular senescence and proinflammatory microenvironments. Mechanistically, WNT10B mediates metabolic reprogramming from fatty acid oxidation to glycolysis, thus promoting cell senescence and cytokine secretion. Genetic ablation of Wnt10b in male CKD mouse model effectively inhibits cell senescence, inflammation, and fibrogenesis by maintaining metabolic homeostasis. Conversely, Wnt10b transgene in tubular cells aggravates metabolic imbalance, and promotes tubular senescence and fibrogenesis. Forkhead box O6 (FOXO6), a DNA-binding transcription factor, mediates the signal transduction cascade of WNT10B. ChIP-, bulk RNA-, and single-nucleus RNA- sequencing and biological assays verify that FOXO6 transcriptionally modulates PPARA and PKM to control metabolic reprogramming and regulate senescence fate transition in tubular cells. Therefore, the study reveals that WNT10B/FOXO6 signaling controls tubular cell senescence fate, and sheds a light on potential intervention targets to protect against CKD. Here the authors report that WNT10B, a ligand of the Wnt family, mediates renal inflammation and fibrosis. Mechanistic work in male mice with induced chronic kidney disease shows that the WNT10B/FOXO6 axis controls tubular senescence fate transition and pro-inflammatory microenviroment formation through metabolic reprogramming.