The emerging Nexus of STING signaling and ferroptosis: from mechanisms to therapeutic opportunities.

Abstract

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a cornerstone of innate immunity, and ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, have traditionally been studied as distinct entities. However, emerging evidence reveals a complex and bidirectional crosstalk between these two pathways with profound implications for disease pathogenesis and therapy. This review systematically synthesizes the current understanding of the multifaceted interactions between the cGAS-STING pathway and ferroptosis. We detail the mechanisms by which STING signaling promotes ferroptosis through iron metabolism (e.g., NCOA4-mediated ferritinophagy), lipid peroxidation (e.g., via ACSL4 interaction), and GPX4 autophagic degradation. Conversely, we explore how ferroptosis, through mitochondrial DNA release and lipid peroxidation products, can activate the cGAS-STING pathway, amplifying immune and inflammatory responses. A novel, non-canonical role for mitochondrially-localized cGAS in suppressing ferroptosis independent of STING is also highlighted, adding a layer of complexity to this interplay. We consolidate evidence of this crosstalk across a spectrum of diseases, including cancer, infectious diseases, neurodegenerative disorders, and ischemia-reperfusion injuries. In cancer, leveraging this interplay-particularly by inducing ferroptosis to activate STING-dependent anti-tumor immunity-presents promising therapeutic strategies. In contrast, for inflammatory and organ injuries, concurrent inhibition of both pathways may mitigate damage. This review underscores the STING-ferroptosis axis as a critical regulatory node and a promising frontier for developing novel therapeutic interventions across diverse human diseases.