Intersection of immune signaling and cell death: The bidirectional regulatory mechanism of STING pathway and Ferroptosis

Abstract

The STING signaling pathway is a central component of the innate immune system, primarily responsible for sensing cytosolic DNA and triggering type I interferon responses to regulate innate immune signaling. Recent studies have revealed that, beyond its roles in immune responses, inflammation, and infection, STING can also regulate metabolism and cell death through classical or non-classical signaling pathways. Ferroptosis, a unique iron-dependent form of cell death characterized by intracellular iron accumulation and lipid peroxidation, has been implicated in various diseases, including cancer, autoimmune diseases, neurodegenerative disorders, and infections. Emerging research has demonstrated a correlation between STING and ferroptosis. STING activation induces the production of inflammatory factors and cytokines, which disrupt iron homeostasis, lipid metabolism, and oxidative balance, thereby triggering ferroptosis. Meanwhile, key proteins like GPX4 and ACSL4 in ferroptosis along with certain metabolic products can also influence the activity of the STING signaling pathway. The regulatory direction and signaling intensity of these interactions significantly impact disease states. As a result, deciphering their molecular mechanisms is critical for developing precise therapeutic strategies. Here, we provide a comprehensive overview of the latest research advances related to the STING signaling pathway and ferroptosis, with a particular emphasis on the molecular mechanisms underlying their mutual regulation. In addition, we discuss therapeutic strategies targeting STING signaling and ferroptosis in disease pathology, thereby highlighting their prospective clinical significance in conditions such as cancer and autoimmune diseases.

Keywords: Cell death; Disease; Ferroptosis; Immunity; Mechanism; cGAS-STING pathway.