cGAS-STING and PANoptosis: Interplay, Underlying Mechanisms, and Therapeutic Targets

Yumin Wang,1, Jinxia Chen,2, Wenxin Feng,3, Ning Li,4 Xiu Zhang,5 Shuang Zhao,6 Kerui Shi,7 Erdan Wang,7 Yuzi Jin7 1Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, People’s Republic of China; 2Department of Blood Transfusion, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 3Department of Anesthesiology, Basic Medical College, Guangxi Medical University, Nanning, People’s Republic of China; 4Department of Biochemistry and Molecular Biology, Shenyang Medical College, Liaoning Province Key Laboratory for Phenomics of Human Ethnic Specificity and Critical Illness(LPKL-PHESCI), Shenyang Key Laboratory for Phenomics, Shenyang, People’s Republic of China; 5Department of Stomatology, Shenyang Medical College, Liaoning Province Key Laboratory for Phenomics of Human Ethnic Specificity and Critical Illness (LPKL -PHESCI), Shenyang Key Laboratory for Phenomics, Shenyang, People’s Republic of China; 6Laboratory Animal Center, Affiliated Hospital of Chengde Medical University, Chengde, People’s Republic of China; 7Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, People’s Republic of ChinaThese authors contributed equally to this workCorrespondence: Yuzi Jin, Email Jinyz@symc.edu.cnAbstract: The cGAS-STING pathway is an essential cytosolic DNA sensing mechanism that activates innate immune responses upon detection of microbial or aberrant self-DNA. This evolutionarily conserved signaling axis plays critical roles in autoimmune diseases, sterile inflammation, and cellular senescence. While its transient activation provides protective immunity, dysregulated cGAS-STING signaling contributes to the pathogenesis of various inflammatory and autoimmune conditions. Growing evidence indicates its functional convergence with multiple cell death pathways—particularly PANoptosis, a distinct inflammatory programmed cell death (PCD) pathway that integrates key features of pyroptosis, apoptosis, and necroptosis. The dynamic interplay between cGAS-STING signaling and PANoptosis has emerged as an important pathogenic mechanism across multiple diseases, revealing new therapeutic opportunities. In this review, we propose a unifying conceptual framework in which cGAS-STING activation functions as a predominant upstream driver of PANoptosis across diverse pathological contexts, orchestrated through a convergent molecular axis involving cytosolic DNA sensing, ZBP1-PANoptosome assembly, and coordinated inflammatory cell death. We begin by outlining the core molecular architecture of the cGAS-STING pathway and its implications in disease. We then examine the mechanisms and pathophysiological consequences of cGAS-STING –PANoptosis crosstalk in various disorders, followed by recent advances in therapeutic strategies specifically targeting this interface. Finally, we discuss translational challenges, such as the poor bioavailability and systemic toxicity of conventional STING agonists, and highlight innovative solutions including nanomedicine-based delivery systems that enable tumor-specific activation while minimizing off-target effects. By highlighting the therapeutic potential of pharmacological modulation at this junction, we identify promising strategies for treating inflammation-associated diseases. The center shows two overlapping sections labeled PANoptosis and cGAS-STING signaling, connected by two opposite-direction arrows. Text near the overlap lists: cytosolic DNA accumulation; activating STING; activating cGAS; upregulation of ZBP1, cleaved caspases, pMLKL, GSDMD. At the top is a label: ZBP1 agonist CBL0137. At the bottom are therapy labels: STING agonist DMXAA, diABZI, cGAMP, STBF plus ADU-S100 plus anti-LAG3; and cGAS/cGAS-STING inhibitor RU.521, SN-011. Around the center are disease callouts with illustrations: Cancer (diffuse large B-cell lymphoma; triple-negative breast cancer) with a tumor-cell cluster; Metabolic inflammation (diabetes; obesity); Digestion system (hepatic injure) with a liver; CNS inflammation (Alzheimer; Parkinson) with a brain; Infection (bacteria; virus; fungus); Respiratory system (acute lung injure; asthma) with lungs.Infographic on PANoptosis and cGAS-STING signaling, showing related diseases and drug targets.Keywords: cGAS-STING, PANoptosis, Programmed cell death, crosstalk