Acetylation of CPT1A reduces fatty acid oxidation and leads to dysfunctional renal tubular mitochondria in diabetic kidney disease

Diabetic kidney disease (DKD), a major diabetic complication driving chronic and end-stage renal disease, involves disrupted proximal tubular energy metabolism. This study investigated the pathogenic role ofcarnitine palmitoyltransferase-1A (CPT1A) acetylation-a mitochondrial enzyme governing the rate-limiting step of fatty acid oxidation (FAO)-in DKD progression. Utilizingdb/dbmice to establishin vivoDKD models, we assessed renal fibrosis via histology/Western blotting and performedproteome-wide acetylation profiling. Parallelin vitroanalyses employed high-glucose (30 mM, 48 h)-treated human proximal renal tubular cells. Functional consequences oflysine 584 (K584) acetylationwere evaluated using lentiviral-mediated K584R point mutation. Results demonstrated: (1) Global protein hyperacetylation in DKD mice, with CPT1A identified as the most significantly hyperacetylated mitochondrial protein; (2) Downregulated CPT1A expression in renal tubular epithelia of both murine and human DKD tissues; (3) Association of CPT1A hyperacetylation with elevated α-smooth muscle actin, fibronectin, and reactive oxygen species (ROS), alongside reduced mitochondrial membrane potential, FAO, and fatty acid synthesis; (4) K584R mutation attenuated CPT1A acetylation, enhancing fatty acid synthase activity and FAO while reducing ROS and fibrosis markers. We conclude thatCPT1A acetylation at K584critically drives DKD pathogenesis and represents a promising biomarker/therapeutic target.