Chlorogenic acid attenuates aortic dissection in atherosclerotic mice by inhibiting ferroptosis via the Nrf2/HO-1/GPX4 axis.

Aortic dissection (AD) represents a critical cardiovascular emergency characterized by high mortality and a lack of effective pharmacological interventions. This study investigates the role of ferroptosis, an iron-dependent regulated cell death characterized by lipid peroxidation, in the pathogenesis of AD, with a particular focus on the therapeutic efficacy of chlorogenic acid (CA), a natural phenolic compound with established antioxidant and anti-inflammatory activities. Using an atherosclerotic male ApoE-/- mouse model subjected to a high-fat diet and angiotensin II infusion, we evaluated the effects of CA treatment (50 or 100 mg/kg/day) on AD incidence, mortality, and various pathophysiological parameters. Our findings indicate that CA significantly reduces AD incidence and mortality in a dose-dependent manner, mitigating aortic medial degeneration, elastic fiber fragmentation, and lipid accumulation. Immunofluorescence co-staining further revealed that CA markedly reduced 4-hydroxynonenal (4-HNE) accumulation in α-smooth muscle actin (α-SMA)-positive mouse aortic vascular smooth muscle cells (MOVAS), confirming VSMC-specific inhibition of ferroptosis. Mechanistically, CA inhibits ferroptotic damage by reducing mitochondrial shrinkage and reactive oxygen species (ROS) production, while restoring the expression of key ferroptosis-related markers in the Nrf2/HO-1/GPX4 signaling axis. Pharmacological inhibition of Nrf2 using ML385 abolished these CA-mediated protective effects, verifying the essential role of Nrf2 signaling in the anti-ferroptotic action of CA. Corroborating these findings, transcriptomic profiling identified ferroptosis as a pivotal driver of AD, and in vitro experiments demonstrated that CA enhances the viability of MOVAS while inhibiting ferroptosis. In conclusion, this study highlights CA as a promising therapeutic agent for preventing and treating AD, elucidating its action via MOVAS specific ferroptosis inhibition through the Nrf2/HO-1/GPX4 axis, thereby suggesting that targeting ferroptosis may offer novel strategies for aortic wall protection in AD.