ALDH2 inhibition reprograms tubular epithelial cell metabolism and promotes renal injury susceptibility

Fatty Acid Oxidation (FAO) dysfunction induces pro-fibrotic transition in tubular epithelial cells (TECs) and contributes to renal fibrosis in chronic kidney disease (CKD); however, the drivers of metabolic reprogramming in TECs remain unclear. We investigate the role of aldehyde dehydrogenase 2 (ALDH2) in FAO using human cohorts, renal tubular Aldh2 knockout mice, Aldh2 rs671 variant mice, and primary TECs, combined with pharmacological and molecular assays. In this work, we find that ALDH2 is downregulated in the injured proximal tubular cells and inversely correlated with lipid deposition and renal fibrosis in CKD patients and mouse models. ALDH2 deletion impairs FAO, leading to lipid deposition and aggravates renal fibrosis following kidney injury, driven by suppression of the key transcription factor PPARα/RXRα complex and its downstream FAO targets, particularly CPT1α. Moreover, ALDH2 deficiency blunts the PPARα agonist Fenofibrate-induced FAO activation and renoprotection. These findings reveal that ALDH2 acts as a mediator of FAO in TECs, making it a potential therapeutic target for CKD. ALDH2 acts as a mediator of fatty acid oxidation (FAO) in tubular epithelial cells (TECs). ALDH2 inhibition triggers FAO dysfunction via downregulation of the PPARα/RXRα-CPT1α pathway and contributes to renal fibrosis in chronic kidney disease (CKD).