Targeting the smooth muscle cell KEAP1-Nrf2-STING axis with pterostilbene attenuates abdominal aortic aneurysm

Background: Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease, and to date, there are currently no effective pharmacological treatments to address this condition. Activation of cytosolic DNA sensing adaptor stimulator of interferon genes (STING) signaling is a crucial mechanism in AAA formation. Purpose: This study investigated pterostilbene (Pt), a naturally occurring polyphenol and resveratrol analogue, as a STING inhibitor for preventing AAA. Methods: We evaluated the effect of Pt on AAA formation in angiotensin II (AngII)-infused apolipoprotein Edeficient (ApoE -/- ) mice. We used histological analysis, MMP activity measurement, western blot, and immunohistochemistry to detect AAA formation and development. We applied RNA sequencing, molecular docking, cellular thermal shift assay (CETSA) and functional studies to dissect the molecular mechanism of Pt-regulating KEAP1-Nrf2-STING signaling. We conditionally knocked down Nrf2 in vascular smooth muscle cells (VSMCs) in vivo to investigate its role in Pt-mediated protective effects on AAA. Results: Pt effectively blocked the formation of AAA in AngII-infused ApoE -/- mice. Whole transcriptome sequencing analysis revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) and STING pathway in VSMCs were linked to the anti-AAA effects of pterostilbene. Mechanistically, Pt upregulated Nrf2 target genes ( e.g. , HO -1 and NQO1) through activation of the KEAP1/Nrf2 signaling, which restricted the immunostimulatory axis of mtDNA-STING-TBK1-NF- kappa B, thereby alleviating VSMC inflammation and preserving the VSMC contractile phenotype. Subsequently, molecular docking and CETSA revealed a binding mode between Pt and KEAP1/Nrf2. Intriguingly, the inhibitory effect of Pt on STING signaling and the protective role of Pt in AAA were largely abrogated by VSMC-specific Nrf2 knockdown in mice. Conclusion: Collectively, naturally derived Pt shows promising efficacy for the treatment of AAA by targeting the KEAP1-Nrf2-STING axis in VSMCs.