MTDH impairs PPARα-mediated fatty acid oxidation to aggravate renal lipotoxicity in diabetic kidney disease

Background Impaired fatty acid oxidation (FAO) inducing lipotoxicity in renal tubules is key in diabetic kidney disease (DKD) progression, yet mechanisms are unclear. Metadherin (MTDH) is linked to DKD but its role in renal lipotoxicity is unknown. Method A DKD mouse model was established via unilateral nephrectomy, high-fat diet, and STZ. Palmitate acid-induced renal tubular epithelial cells were also used. Renal MTDH in mice was knocked down using AAV9, and MTDH was silenced or overexpressed in vitro. Result In mice, MTDH knockdown improved renal function, enhanced FAO via PPARα, and reduced lipid toxicity. In vitro, MTDH silencing mitigated lipid accumulation and activated FAO, while overexpression aggravated injury, reversed by PPARα agonist. Conclusion MTDH upregulation in diabetic kidney disrupts lipid homeostasis by repressing PPARα-mediated FAO, promoting lipotoxic injury, offering new insights into DKD metabolic dysregulation.