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

OBJECTIVE: The current study is aimed at elucidating the mechanisms underlying the involvement of ferroptosis in atherosclerosis (AS) and exploring potential therapeutic targets. METHODS: 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. RESULTS: 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 Fe(2+) 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. CONCLUSION: HTR2B suppressed ferroptosis by promoting the PI3K/AKT axis, enhanced cellular viability, and exhibited a protective role in AS.