Dehydrocorydaline Promotes STAT3 /Bcl‐2 Axis‐Mediated Macrophage Efferocytosis to Attenuate Apoptosis in Atherosclerotic Plaques

ABSTRACT Interleukin 4 (IL‐4)‐mediated apoptosis is involved in the pathogenesis of atherosclerosis both through efferocytosis overload and direct cellular signalling pathways. This study explored the mechanism of dehydrocorydaline (DHC), a potential therapeutic agent for atherosclerosis derived from Corydalis yanhusuo . An experimental model of atherosclerosis was established in high‐fat diet‐induced ApoE −/− mice, with DHC intervention administered during the final 4 weeks of the protocol. We used an integrated approach combining molecular docking, molecular dynamics and target validation through microscale thermophoresis to elucidate the molecular mechanisms underlying the antiatherosclerotic effects of DHC. The experimental results demonstrated that DHC exerted significant antiatherosclerotic effects in atherosclerotic mice, primarily through attenuation of pathological apoptosis within plaques and suppression of inflammatory responses. Subsequent molecular analysis revealed that DHC binds strongly to signal transducer and activator of transcription 3 (STAT3). DHC treatment mitigated dysregulated efferocytosis secondary to apoptotic overload and inflammatory responses in macrophages both in vivo and in vitro, cultured by specifically inhibiting the IL‐4‐activated STAT3/Bcl‐2 axis. This study demonstrates that DHC exerts anti‐atherosclerotic effects by reprogramming macrophage fate to restore efferocytosis. Mechanistically, DHC uncouples STAT3 phosphorylation from its transcriptional output, reducing overall p‐STAT3 while specifically enhancing its binding to the Bcl‐2 promoter to upregulate this pro‐survival gene. This dual action modulates global STAT3 activity while potentiating a local survival signal and rebalances the apoptosis‐efferocytosis axis. Our results elucidate a novel pharmacological strategy of context‐dependent STAT3 pathway modulation and highlight DHC as a promising therapeutic candidate for stabilising atherosclerotic plaques.