Myeloid STING-ZBP1 Axis Drives Atherosclerosis by Inducing Macrophage PANoptosis

Abstract Atherosclerosis is a chronic inflammatory disease in which dysregulated programmed cell death (PCD) critically contributes to plaque progression and instability. PANoptosis, an integrated inflammatory cell death pathway encompassing apoptosis, pyroptosis, and necroptosis, has recently emerged as a key regulator of inflammatory diseases. However, its contribution to atherosclerosis and the underlying regulatory mechanisms remain poorly defined. Here, we combined single-cell RNA sequencing (scRNA-seq) to characterize the expression of the stimulator of interferon genes (STING) in human and murine atherosclerotic lesions. Functional studies were conducted using high-fat diet (HFD)-fed ApoE −/− mice with myeloid STING activation or genetic deletion, while RNA sequencing and CUT&Tag sequencing were further employed to elucidate the molecular mechanisms linking STING signaling to Z-DNA-binding protein 1 (ZBP1)-mediated PANoptosis. We found that STING was predominantly expressed in macrophages and was markedly upregulated in both human and murine atherosclerotic lesions. Myeloid-specific STING activation promoted macrophage PANoptosis and exacerbated atherosclerotic plaque formation, whereas STING deficiency markedly attenuated these pathological changes. Mechanistically, STING activated NF-κB signaling and transcriptionally induced ZBP1, thereby triggering macrophage PANoptosis. Importantly, genetic silencing of ZBP1 effectively inhibited PANoptosis and mitigated atherosclerotic lesion progression. Collectively, our findings establish the STING-ZBP1 signaling cascade as a central regulator of macrophage PANoptosis during atherogenesis and uncover a previously unrecognized mechanism linking innate immune signaling to inflammatory cell death in atherosclerosis, highlighting this pathway as a promising therapeutic target for atherosclerotic cardiovascular disease.