WDFY4 Promotes the Progression of Atherosclerosis by Regulating Ferroptosis Mediated by the...

Atherosclerosis (AS) is a prevalent chronic inflammatory cardiovascular disease and leading cause of death worldwide. WD repeat and FYVE domain-containing 4 (WDFY4), a susceptibility gene for autoimmune diseases and reported AS hub gene, is associated with ferroptosis and inflammation. However, the mechanism by which WDFY4 affects atherosclerosis remains unclear. Here, WDFY4 was upregulated in oxidised low-density lipoprotein (ox-LDL)-treated cells and high-fat diet (HFD)-fed ApoE^-/- mice. Endothelium-specific transgenic mice were employed to disrupt the expression level of WDFY4 in vivo. WDFY4 knockdown inhibited ox-LDL-induced ferroptosis, cell injury and inflammation in HAECs in vitro. The STRING database predicted lysosomal transmembrane protein 5 (LAPTM5) as a WDFY4-interacting partner, validated by co-immunoprecipitation (Co-IP) and immunofluorescence co-localisation. Mechanistically, WDFY4 interference inhibited LAPTM5 expression and activated the downstream CDC42/mTOR/4EBP1/SLC7A11 pathway. LAPTM5 overexpression or ML141 (a CDC42 inhibitor) rescued the WDFY4 knockdown-mediated inhibition of ferroptosis, cell damage and inflammation in model cells. WDFY4 or LAPTM5 knockdown reduced plaque formation, lipid deposition and pro-inflammatory factors in vivo. Finally, mice with endothelial-specific WDFY4 knockout were protected against atherosclerosis. Thus, WDFY4 affects ferroptosis-related AS via the LAPTM5/CDC42/mTOR/4EBP1/SLC7A11 pathway. These findings identify a novel role for WDFY4 in AS and its potential as a therapeutic target.