Understanding the role of cGAS-STING signaling in ischemic stroke: a new avenue for drug discovery

INTRODUCTION: Ischemic stroke is a significant global health challenge with limited treatment options. Neuroinflammation, driven by microglial activation, plays a critical role in stroke pathophysiology. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a key player in microglial activation, sterile neuroinflammation, and cell death following stroke. Understanding the interplay between this pathway and stroke pathophysiology is crucial for exploring newer therapeutics for stroke patients. AREAS COVERED: This review discusses the pivotal role of the cGAS-STING pathway in ischemic stroke. It explores the interplay between cGAS-STING activation, neuroinflammation, microglia activation, M2 polarization, neutrophil infiltration, and cytokine release. Additionally, the authors examine its contributions to various cell death programs (pyroptosis, apoptosis, necroptosis, lysosomal cell death, autophagy, and ferroptosis). The review summarizes recent studies on targeting cGAS-STING signaling in stroke, highlighting the therapeutic potential of small molecule inhibitors and RNA-based approaches in mitigating neuroinflammation, preventing cell death, and improving patient outcomes. EXPERT OPINION: Understanding cGAS-STING signaling in ischemic stroke offers an exciting avenue for drug discovery. Targeting this pathway holds promise for developing novel therapeutics that effectively mitigate neuroinflammation, prevent cell death, and enhance patient outcomes. Further research and development of therapeutic strategies are warranted to fully exploit the potential of this pathway as a therapeutic target for stroke.