Metadherin Impairs PPARα ‐Mediated Fatty Acid Oxidation to Aggravate Renal Lipotoxicity in Diabetic Kidney Disease

Impaired fatty acid oxidation (FAO) and subsequent lipotoxicity in renal tubules play a key role in diabetic kidney disease (DKD) progression; however, the underlying mechanisms remain unclear. Metadherin (MTDH) is linked to DKD; however, its potential role in renal lipotoxicity remains poorly characterized. A DKD murine model was established via unilateral nephrectomy, a high‐fat diet, and streptozotocin (STZ) injection. Palmitic acid (PA)‐stimulated renal tubular epithelial cells (RTECs) were also used. Renal MTDH in mice was knocked down using an adeno‐associated virus serotype 9 (AAV9) vector, and MTDH was silenced or overexpressed in vitro. In mice, MTDH knockdown improved renal function, enhanced FAO via peroxisome proliferator‐activated receptor alpha (PPARα), and reduced lipotoxicity. In vitro, MTDH silencing mitigated lipid accumulation and activated FAO, whereas overexpression aggravated the injury, an effect that was reversed by a PPARα agonist. In conclusion, MTDH upregulation in the diabetic kidney disrupts lipid homeostasis by repressing PPARα‐mediated FAO, thereby promoting lipotoxic injury. These findings offer new insights into DKD metabolic dysregulation.