EEPD1 Deficiency Drives Diabetic Kidney Disease Progression via Amplified Genotoxic Stress and Downregulation of EHHADH

Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by oxidative stress and chronic inflammation that collectively promote cellular DNA damage and tubular injury. Although these pathological mechanisms are well recognized, the contribution of DNA repair enzymes to DKD progression remains largely unexplored. Here, we identify endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1), a key DNA damage response enzyme, as a novel renoprotective factor in DKD. We found that EEPD1 protein abundance was significantly reduced in the kidneys of high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice and db/db mice (two widely used murine models of DKD) and in human proximal tubular epithelial cells (HK-2) exposed to high glucose. Genetic ablation of Eepd1 in mice exacerbated renal injury, fibrosis, and dysfunction in both HFD/STZ-induced and HFD-induced diabetic models. Transcriptomic and biochemical analyses revealed that Eepd1 deficiency promoted DNA damage accumulation, inflammatory activation, and metabolic dysregulation, particularly through suppression of the peroxisomal fatty acid oxidation (FAO) enzyme EHHADH, at both mRNA and protein levels. Integrated transcriptional analyses and functional validation further identified PPARα as a critical transcriptional mediator linking EEPD1 to EHHADH regulation. Mechanistically, EEPD1 deficiency reduced PPARα expression, whereas PPARα depletion impaired EEPD1-dependent activation of EHHADH expression and promoter activity. Collectively, our findings identify an EEPD1–PPARα–EHHADH regulatory axis that connects DNA repair with peroxisomal metabolic homeostasis and establishes EEPD1 as a potential therapeutic target for DKD.