Lysine-374 lactylation of TFRC is essential for TFRC-mediated kidney tubular ferroptosis in diabetic kidney disease

Diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, lactate overload and ferroptotic kidney injury, yet the mechanistic link between lactylation and ferroptosis remains undefined. Using lactylome profiling of db/db mouse kidneys, we identified transferrin receptor (TFRC) as the key ferroptosis regulator modified by lactylation. Here we explore the pathogenic role of TFRC lactylation in DKD progression. We observed significantly elevated lactate levels and specific lactylation of TFRC at lysine 374 (K374) in the kidneys of db/db mice and lactate-stimulated HK2 cells. This modification was strongly correlated with increased iron accumulation, lipid peroxidation, and kidney fibrosis. Mechanistically, through screening of canonical lactylation-associated enzymes, we identified histone acetyltransferase p300 as the major enzyme catalyzing TFRC K374 lactylation. Utilizing a non-lactylatable TFRC mutant (K374R), we demonstrated that preventing this modification represses lactate-induced ferroptosis and profibrotic signaling both in vitro and in vivo. Virtual screening of an endogenous compound library identified lysicamine as a p300 inhibitor, which effectively reduced TFRC lactylation and mitigated kidney injury and fibrosis. Collectively, these findings uncover a critical "lactate-p300-TFRC lactylation" axis that drives ferroptosis in DKD, suggesting that targeting TFRC K374 lactylation offers a novel therapeutic strategy for preserving kidney injury in diabetic patients.