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

Area of Science:

• Nephrology
• Molecular Biology
• Pathology

Background:

• Renal fibrosis (RF) is a key feature of chronic kidney disease (CKD), posing a significant healthcare burden.
• Identifying novel therapeutic targets for RF is crucial for managing CKD.

Purpose of the Study:

• To investigate the role of Fat mass and obesity-associated (FTO) in renal fibrosis and ferroptosis.
• To explore FTO inhibition as a potential therapeutic strategy for obstruction-related kidney injury.

Main Methods:

• Utilized mouse models with unilateral ureteral obstruction (UUO) and sham operations.
• Employed murine and human kidney epithelial cells, and human embryonic stem cell-derived kidney organoids.
• Assessed collagen deposition, lipid peroxidation, ferroptosis markers (e.g., ACSL4), TGFBI expression, and M2 macrophage accumulation.

Main Results:

• FTO inhibition significantly reduced collagen deposition, lipid peroxidation, and ferroptosis markers in UUO mice.
• FTO inhibition decreased erastin-induced ferroptosis by downregulating ACSL4, reducing lipid peroxidation and reactive oxygen species.
• FTO inhibition downregulated TGFBI, correlating with reduced M2 macrophage accumulation post-UUO.

Conclusions:

• FTO inhibition demonstrates a strong therapeutic potential for alleviating renal fibrosis in obstruction-related kidney injury.
• Targeting FTO may reduce CKD prevalence, healthcare costs, and improve patient quality of life.