390-P: NCOA4-FTH1 Axis Regulates Iron Homeostasis and Ferroptosis in Diabetic Kidney Disease

Introduction and Objective: To investigate the role of the NCOA4-FTH1 axis in regulating iron metabolism, ferroptosis, and fibrosis in diabetic kidney disease (DKD) and explore its potential as a therapeutic target. Methods: We utilized db/db mice and renal cells cultured under high-glucose and high-fat conditions to establish in vivo and in vitro DKD models. Oxidative stress, ferrous iron, lipid peroxidation, iron metabolism genes, and fibrosis markers were evaluated using biochemical assays, immunofluorescence, and Western blotting. The effects of NCOA4 knockdown, FTH1 deficiency, and treatment with HIF-1 inhibitors (YC-1) or metformin were assessed on ferroptosis and fibrosis. Results: Renal tissues from DKD mice and DKD cell model exhibited iron overload, especially ferrous iron, along with elevated lipid peroxidation and mitochondrial changes indicative of ferroptosis, and dysregulated NCOA4 and FTH1 expression. Knocking down FTH1 promoted ferroptosis and fibrosis, while NCOA4 knockdown under high glucose and lipid conditions restored FTH1 levels, inhibiting ferroptosis and fibrosis. Elevated NCOA4 in DKD mice correlated with HIF-1αexpression, and in vitro hypoxia increased HIF-1α and NCOA4. Treatment with YC-1 or metformin reduced HIF-1α and NCOA4 expression, attenuating intracellular lipid peroxidation and ferroptosis in renal tubular cells. Conclusion: This study identifies the NCOA4-FTH1 axis as a critical regulator of iron metabolism and ferroptosis in DKD. Targeting this pathway can mitigate oxidative stress and fibrosis, providing a novel therapeutic strategy for DKD. Disclosure X. Chen: None. M. Zhang: None. Funding National Natural Science Foundation of China (82370828); the Improvement of Clinical Ability Project of Jiangsu Province Hospital (JSPH-MA-2021-3)