Background: Endothelial dysfunction is a pivotal contributor to coronary heart disease (CHD). The study aimed to elucidate the involvement of YT521-B homology domain 1 (YTHDF1) in mediating endothelial dysfunction triggered by oxidized low-density lipoprotein (ox-LDL) in human coronary artery endothelial cells (HCAECs).

Methods: Cell viability was evaluated using the Cell Counting Kit-8 (CCK-8) assay, while apoptotic status was determined by flow cytometric analysis. Cell migratory capacity was examined through a Transwell assay. The concentrations of pro-inflammatory cytokines (Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, and IL-18) together with the adhesion molecule VCAM-1 were measured using Enzyme-linked immunosorbent assay (ELISA). Intracellular Reactive oxygen species (ROS) production was assessed via DCFH-DA fluorescent staining. The N6-methyladenosine (m⁶A) modification level of BTB and CNC homology 1 (BACH1) was analyzed using Methylated RNA binding protein immunoprecipitation (MeRIP), and molecular interactions were further explored using RNA binding protein immunoprecipitation (RIP) assay.

Results: YTHDF1 expression was significantly increased in peripheral blood mononuclear cells (PBMCs) from CHD patients compared with healthy controls and in ox-LDL-treated HCAECs compared with untreated cells (p < 0.05). YTHDF1 silencing significantly attenuated ox-LDL-induced endothelial injury, as evidenced by increased cell viability and migration and decreased apoptosis, inflammatory cytokine secretion, and ROS production (all p < 0.05). Mechanistically, YTHDF1 promoted BACH1 mRNA translation in HCAECs in an m⁶A-dependent manner (p < 0.05). Furthermore, BACH1 overexpression significantly reversed the protective effects of YTHDF1 knockdown on HCAEC survival and migration and restored ox-LDL-induced oxidative stress and inflammatory responses (p < 0.05).

Conclusion: YTHDF1 promoted ox-LDL-induced HCAEC dysregulation by enhancing BACH1 mRNA translation in an m⁶A-dependent manner.