ACSM3 deficiency impaired medium-chain fatty acid metabolism and aggravated kidney fibrosis [RNA-Seq]

Kidney fibrosis is driven by multiple pathogenic factors, among which impaired fatty acid oxidation has emerged as a critical determinant. Acyl-CoA synthetase medium-chain family member 3 (ACSM3), a key enzyme involved in medium-chain fatty acid (MCFA) metabolism, has been implicated in metabolic syndrome, but its function in fibrotic kidney remains unexplored. Here, we found that tubular epithelial ACSM3 expression was downregulated in kidney fibrotic mice and patients, and inversely correlated with disease severity. Systemic or tubular-specific knockout of ACSM3 both exacerbated renal fibrosis, whereas AAV-mediated ACSM3 overexpression alleviated fibrosis progression in mice. Mechanically, ACSM3 deficiency results in abnormal mitochondrial homeostasis and disrupted MCFA metabolism. Notably, we identified that dodecanoic acid (C12:0) could delay kidney fibrosis and was primarily utilized via ACSM3 in kidneys. Furthermore, dodecanoic acid oxidation impairment caused by ACSM3 deficiency contributed to fibrotic kidney progression. Together, ACSM3-reguated MCFA metabolism played a pivotal role in kidney fibrosis pathogenesis, highlighting a potent therapeutic target against chronic kidney diseases.