Folic acid alleviates endothelial dysfunction caused by T2DM-induced ferroptosis by activating the SIRT6/NRF2/GPX4 signaling pathway.

Cardiovascular complications associated with type 2 diabetes mellitus (T2DM) pose a serious threat to human health. Folic acid deficiency is associated with various diseases, including atherosclerosis. However, it remains unclear whether folic acid has a protective effect on vascular injury induced by T2DM. To address this, folic acid was administered to db/db or db/dm mice, and endothelial cells were treated under high-fat and high-glucose (HGF) conditions to evaluate the effect of folic acid on cell viability. RNA sequencing was performed to explore the potential targets of folic acid. The results indicated that folic acid alleviates endothelial cell injury and ferroptosis in T2DM by upregulating the SIRT6/NRF2 pathway and mitigating oxidative stress, Fe2+ accumulation and lipid peroxidation. The SIRT6 inhibitor counteracted the protective effect of folic acid on endothelial cells in vitro. Overall, folic acid may be a promising drug for treating or alleviating endothelial dysfunction in T2DM.