Metadherin Drives FOXO3a Lactylation and Mitochondrial Dysfunction to Promote Podocyte Injury in Diabetic Kidney Disease

Diabetic kidney disease (DKD) involves abnormal glucose metabolism and mitochondrial dysfunction. Metabolic reprogramming contributes to DKD progression, but the underlying mechanisms are unclear. Here, we report that metadherin (MTDH) drives podocyte injury via metabolic reprogramming. MTDH expression was assessed in kidney biopsy specimens from DKD patients. Podocyte-specific Mtdh knockout mice were generated and challenged with streptozotocin to evaluate podocyte injury. Targeted metabolomics, RNA sequencing, Seahorse analysis, and coimmunoprecipitation (co-IP) were performed. Our results show that MTDH was increased in podocytes of DKD patients and correlated with proteinuria. Podocyte-specific Mtdh deletion reduced proteinuria, podocyte injury, and glomerulosclerosis in diabetic mice. Mechanistically, MTDH enhanced glycolysis but suppressed the tricarboxylic acid cycle. Among glycolytic enzymes, only lactate dehydrogenase A (LDHA) was elevated by MTDH. This led to lactate accumulation and podocyte injury, which were reversed by LDHA silencing. MTDH-driven lactate induced FOXO3a lysine lactylation and nuclear translocation. This selectively activated proapoptotic genes (FasL and Bim) and repressed proautophagy (Beclin1 and ATG5) and antioxidant (SOD2) genes. Additionally, MTDH reduced oxidative phosphorylation and mitochondrial gene expression. Podocyte-specific Mtdh deletion restored mitochondrial metabolism and reduced mitochondrial injury. In contrast, MTDH overexpression exacerbated mitochondrial damage via pyruvate kinase M2 (PKM2). Co-IP showed that MTDH bound to PKM2 and disrupted PKM2–mitofusin 2 (MFN2) interaction, thereby inhibiting mitochondrial fusion. Together, MTDH drives podocyte injury in DKD through two integrated mechanisms: LDHA-mediated FOXO3a lactylation that reprograms transcriptional activity and PKM2-MFN2 disruption that impairs mitochondrial fusion. These findings position MTDH as a central metabolic regulator and a promising therapeutic target for DKD. Article Highlights This study investigated whether metadherin (MTDH) drives podocyte injury in diabetic kidney disease through metabolic reprogramming. We sought to define the molecular mechanisms linking altered glucose metabolism to podocyte mitochondrial dysfunction. We found that MTDH upregulates lactate dehydrogenase A, leading to lactate-driven FOXO3a lactylation that selectively activates proapoptotic genes and disrupts pyruvate kinase M2-mitofusin 2 interaction, impairing mitochondrial fusion. These findings identify MTDH as a central metabolic regulator and suggest that targeting MTDH-mediated pathways, including FOXO3a lactylation and pyruvate kinase M2-mitofusin 2 disruption, may represent a promising therapeutic strategy for diabetic kidney disease.