Transcriptome Insights into Protective Mechanisms of Ferroptosis Inhibition in Aortic Dissection

Aortic dissection (AD) is a life-threatening vascular condition with limited pharmacological options, and shared risk factors with cardiac disease include hypertension, atherosclerosis, smoking, and dyslipidemia. This study investigated Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, in a BAPN/Ang-II-induced mouse model of AD, revealing significant therapeutic potential. Fer-1 significantly reduced AD incidence and mortality by preserving aortic wall integrity. RNA sequencing identified 922 differentially expressed genes, with 416 upregulated and 506 downregulated. Bioinformatics analysis revealed that Fer-1 modulates key regulators, such as <i>MEF2C</i> and <i>KDM5A</i>, impacting immune responses, oxidative stress, apoptosis, and lipid metabolism. Additionally, Fer-1 alters miRNA expression, with the upregulation of miR-361-5p and downregulation of miR-3151-5p, targeting pathways involved in inflammation, oxidative stress, and smooth muscle cell (SMC) phenotypic stability. Functional pathway analysis highlighted the inhibition of actin cytoskeleton, <i>ILK</i>, and <i>IL-17</i> signaling, essential for SMC differentiation and extracellular matrix remodeling. Gene interaction network analysis identified 21 central molecules, including <i>CXCR3</i>, <i>ACACA</i>, and <i>BPGM</i>, associated with lipid metabolism, inflammation, and vascular remodeling. This research elucidates the mechanism of ferroptosis in AD pathogenesis and establishes Fer-1 as a promising therapeutic intervention. AD and cardiac diseases share molecular mechanisms, risk factors, and pathological processes, positioning AD within the broader scope of cardiovascular pathology. By attenuating lipid peroxidation, oxidative stress, and inflammation, Fer-1 may have cardioprotective effects beyond AD, providing a foundation for future translational research in cardiovascular medicine.