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.