HTR2B-Mediated Endothelial Protection: Modulating Ferroptosis via the PI3K/AKT Signaling Pathway in Atherosclerosis

The current study is aimed at elucidating the mechanisms underlying the involvement of ferroptosis in atherosclerosis (AS) and exploring potential therapeutic targets.

Endothelial function and lipid peroxidation were assessed in vitro using HCAECs treated with OX-LDL. SLC7A11, GPX4, TfR1, and FTH1 were analyzed by western blot, respectively. Representative markers of ferroptosis including LDH, MDA, 4-HNE, GSH, and iron content were detected. HTR2B miRNA (OE-HTR2B) and controls (OE-NC, empty vector) were transfected. AS was induced in ApoE^-/- mice through a high-fat diet. The effect of ferroptosis inhibition on atherosclerotic lesion development was evaluated by different inhibitor treatments.

RNA-Seq analysis revealed dysregulated HTR2B expression in HCAECs exposed to OX-LDL, indicating its involvement in AS pathogenesis. OX-LDL exposure reduced cell viability and induced ferroptosis, characterized by decreased SLC7A11 and GPX4 expression and increased lipid peroxidation. Overexpression of HTR2B rescued cell viability, reduced Fe²⁺ accumulation, and upregulated SLC7A11 and GPX4, suggesting a protective role against ferroptosis. Further, HTR2B regulated ferroptosis via the PI3K/AKT pathway, as evidenced by changes in pathway protein phosphorylation. By activating HTR2B with an agonist BW-723C86, we verified that HTR2B can inhibit ferroptosis through the PI3K/AKT pathway in an atherosclerotic mouse model.

HTR2B suppressed ferroptosis by promoting the PI3K/AKT axis, enhanced cellular viability, and exhibited a protective role in AS.