Crosstalk between cGAS-STING and pyroptosis: From molecular mechanisms to therapeutic strategies

Abstract

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling axis is an evolutionarily conserved mechanism that detects cytoplasmic nucleic acids and orchestrates innate immune responses against pathogens and endogenous DNA damage. This sophisticated detection system not only mediates antimicrobial defense but also emerges as a central modulator in autoimmune pathogenesis, sterile inflammation, and senescence-associated secretory phenotypes.Recent discoveries reveal functional interconnections between cGAS -STING signaling and regulated cell death pathways, especially pyroptosis. We first outline the core molecular components of the cGAS-STING pathway and pyroptosis. We then explain the mechanisms and pathological relevance of cGAS-STING-pyroptosis crosstalk in various diseases, integrating structural and cellular insights. We also discuss recent advances in therapeutic strategies that target this crosstalk, highlighting new drugs and conceptual frameworks. Notably, we propose a conceptual framework categorizing therapeutic interventions into three tiers: Upstream nucleic acid sensing regulation, core pathway modulation, and downstream effector control.This review highlights the therapeutic potential of targeting the cGAS -STING-pyroptosis axis in multiple diseases. It also outlines promising treatment paradigms for multiple disease entities. This review provides a roadmap for developing next-generation therapies leveraging the cGAS-STING-pyroptosis axis, with particular emphasis on combinatorial approaches and biomarker-guided personalized intervention strategies.

Keywords: Antagonist; Crosstalk; Pyroptosis; STING; cGAS.