<scp>EIF2α</scp> – <scp>ATF4</scp> – <scp>CHAC1</scp> Signalling Links <scp>ER</scp> Stress to Ferroptosis in Human Aortic Smooth Muscle Cells: Mechanistic Insights and Therapeutic Implications

pool; ferrostatin-1 mitigated these changes. BSO further amplified p-PERK→p-EIF2α → ATF4 → CHAC1 signalling and deepened GPX4 loss, whereas salubrinal sustained EIF2α phosphorylation, augmented ATF4/CHAC1, and further depressed GPX4. Across conditions, effects were consistent in both cell types and reached statistical significance (most p < 0.05 to < 0.01). ER-stress signalling via PERK-EIF2α-ATF4-CHAC1 constitutes a proximal driver of ferroptosis in human aortic SMCs by eroding glutathione tone and disabling GPX4, thereby promoting lipid peroxidation in an iron-rich milieu. Pharmacologic tuning of EIF2α phosphorylation and glutathione biosynthesis modulates ferroptotic susceptibility, nominating EIF2α-ATF4-CHAC1, GPX4/GSH homeostasis and iron handling as actionable nodes to preserve VSMC integrity in oxidizing vascular environments.