FTO inhibition attenuates renal fibrosis by downregulating ferroptosis activator ACSL4 and profibrotic factor TGFBI.

Renal fibrosis (RF) is the main pathological feature and a potential therapeutic target of chronic kidney disease (CKD), a prevalent health problem causing a high economic burden to the health care system. Fat mass and obesity-associated (FTO) inhibition, either genetically or pharmacologically, significantly reduced collagen deposition, lipid peroxidation, and ferroptosis marker expression after unilateral ureteral obstruction (UUO) compared with sham-operated controls in mice. In murine and human kidney epithelial cells as well as in human embryonic stem cell-derived kidney organoids, FTO inhibition reduced erastin-induced ferroptosis by decreasing lipid peroxidation and reactive oxygen species production by downregulating the ferroptosis driver ACSL4. Moreover, FTO inhibition directly downregulated TGFBI, which was strongly associated with reduced M2 macrophage accumulation after UUO. Our results provide a strong rationale for targeting FTO to alleviate RF in patients subjected to obstruction-related kidney injury, thereby reducing the prevalence of CKD and associated treatment costs and improving the quality of life.