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

ABSTRACTIntroduction 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.KEYWORDS: cGASSTINGneuroinflammationstrokeneurodegenerative disordersimmune response Article highlights cGAS is a cytosolic enzyme that senses dsDNA and orchestrates the innate immune response by activating cGAMP-dependent STING signaling.Accumulation of dsDNA in the cytosol or extracellularly during stroke triggers the cGAS-STING cascade, contributing significantly to the pathophysiology of ischemic stroke.Activation of cGAS-STING signaling regulates microglia activation, M2 polarization neutrophil infiltration, and cytokine release, shaping the post-ischemic neuroinflammatory response.The cGAS-STING pathway is involved in various cell death programs, including pyroptosis, apoptosis, necroptosis, lysosomal cell death, autophagy, and ferroptosis.Targeting the cGAS-STING pathway holds promise for stroke treatment, with selective inhibitors and RNA therapeutics demonstrating efficacy in reducing inflammation and improving stroke outcomes.Continued research into the cGAS-STING pathway is essential for advancing therapeutic strategies and improving outcomes in ischemic stroke.AcknowledgmentsThe corresponding author would like to acknowledge and express gratitude to the Science and Engineering Research Board, Department of Science and Technology, Government of India, for the financial support provided to the stroke research conducted in his laboratory.Declaration of interestThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresOne reviewer declares that they are a former employee and consultant for Evotec who has their own drug discovery consultancy company. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Additional informationFundingRK Kaundal has been granted funds for stroke research by the Science and Engineering Research Board, a division of the Department of Science and Technology of the Government of India.