STING-ERO1 signaling exacerbates PARylation-mediated parthanatos in sepsis

Sepsis is a life-threatening condition characterized by uncontrolled inflammation, oxidative stress, and aberrant cell death. Although the STING pathway is well established as a central mediator of innate immunity, its functions beyond interferon signaling remain largely undefined. Here, we investigated a noncanonical STING–ERO1–PARP1 axis that drives oxidative damage and Parthanatos during sepsis. A combination of in vivo and in vitro approaches was employed to dissect the STING–ERO1–PARP1 signaling cascade. A sepsis model was established via cecal ligation and puncture, and various genetic knockout mice (STING⁻/⁻, cGAS⁻/⁻, and IFNAR1⁻/⁻) were used to assess pathway specificity. In vitro studies in RAW264.7 and iBMDM cells involved STING agonist stimulation combined with genetic knockouts (STING⁻/⁻, TBK1⁻/⁻), targeted inhibitors (PJ34, EN460, NAC), and siRNA transfection to dissect signaling mechanisms. Molecular and cellular responses were evaluated by immunoblotting, immunofluorescence, ELISA, TUNEL staining, and ROS detection. Cell death, cytokine expression, and tissue injury were quantified via standard assays. we demonstrated that the STING signaling axis drives parthanatos and intestinal injury through endoplasmic reticulum (ER) oxidative stress. Mechanistically, STING directly interacts with ER oxidoreductase 1 (ERO1), inducing oxidative stress and cytosolic ROS accumulation, which triggers DNA damage, PARP1 hyperactivation, and excessive PARylation. This cascade promotes the nuclear translocation of apoptosis-inducing factor (AIF) and Parthanatos. Notably, this mechanism occurred independently of the canonical cGAS–TBK1–interferon axis. Genetic deletion or pharmacological inhibition of STING, ERO1, or PARP1 significantly reduces ROS levels, PARylation, and intestinal injury. We identified a novel STING–ERO1–PARP1 signaling cascade that links innate immune sensing to redox dysregulation and cell death, providing new therapeutic targets for mitigating organ injury in sepsis.