Urolithin A Mitigates Renal Fibrosis by Promoting Fatty Acid Oxidation Through Orchestrating β-Catenin Signaling.

Kidney fibrosis, a progressive outcome of various chronic kidney diseases (CKD), features tubule atrophy, chronic interstitial inflammation, and abnormal metabolic changes. Urolithin A (UA), a gut microbiome metabolite derived from ellagic acid and ellagitannins, has anti-inflammatory and anti-obesity effects and enhances cellular health by promoting mitophagy and mitochondrial function. This study aimed to evaluate the protective effects of UA against renal fibrosis in mice with unilateral ureteral obstruction (UUO) and to investigate its underlying mechanisms. UA significantly reduced lipid deposition and mitigated renal fibrosis in the kidneys of UUO mice and TGFβ1-induced HK-2 cells. Mechanistically, UA alleviated renal fibrosis by inhibiting GSK3β/β-catenin signaling to promote FAO, rather than through the canonical TGF-β1/Smad or Notch1 signaling pathways. Furthermore, UA activates GSK3β to inhibit β-catenin via AKT1 but independent of SIRT3 or PP2A. Altogether, UA significantly mitigated kidney fibrosis by restoring fatty acid oxidation metabolism through inactivation of the GSK3β/β-catenin axis, offering potential as an alternative therapy to combat renal fibrosis.