Interplay of cGAS-STING and ferroptosis: crosstalk, molecular mechanisms, and therapeutic prospects

Abstract

The cGAS-STING pathway, a crucial cytosolic DNA sensor, initiates innate immune responses by detecting microbial and aberrant self-DNA. This evolutionarily conserved axis plays pivotal roles in autoimmune disorders, sterile inflammation, and cellular senescence. While transient activation confers protective immunity, dysregulated cGAS-STING signaling drives pathogenesis in inflammatory and autoimmune diseases. Emerging evidence reveals its functional convergence with diverse cell death modalities-notably ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation. Their dynamic interplay emerges as a key pathogenic mechanism across diseases, offering novel therapeutic opportunities. This review first outlines the core molecular architecture of cGAS-STING signaling and its disease roles. We then analyze the mechanisms and pathophysiological consequences of cGAS-STING-ferroptosis crosstalk in various disorders, followed by advances in therapeutic strategies targeting this interface. Finally, we discuss translational challenges and propose innovative solutions. By highlighting the therapeutic potential of pharmacologically modulating this nexus, we identify a promising treatment for diseases with inflammatory conditions.

Keywords: Antagonist; Ferroptosis; Inhibitor; Interplay; cGAS-STING.