Acupuncture in Cerebral Ischemia-Reperfusion Injury: A Mechanistic Narrative Review of Innate Immune Sensing and Regulated Cell Death-Related Inflammatory Amplification
Abstract
Abstract Cerebral ischemia-reperfusion injury (CIRI) can continue after recanalization because disruption of neurovascular-unit compartmental integrity exposes damage-associated molecular patterns (DAMPs) and couples innate immune sensing to regulated cell death. This mechanism-oriented narrative review integrates CIRI biology with experimental evidence on acupuncture while distinguishing pathway association from mechanistic necessity. HMGB1-TLR4 signaling, extracellular ATP-P2X7 signaling, and aberrant DNA sensing can translate tissue damage into inflammatory transcription, inflammasome activation, and interferon-related responses. Pyroptosis, necroptosis, and ferroptosis can further amplify inflammatory and oxidative injury through membrane-pore formation or rupture, release of intracellular contents, and lipid peroxidation. Acupuncture-specific mechanistic evidence derives predominantly from electroacupuncture in rodent middle cerebral artery occlusion/reperfusion models. Functional support is comparatively stronger for α7 nicotinic acetylcholine receptor-dependent signaling, caspase-1/GSDMD-related pyroptotic execution, Nrf2-SLC7A11/GPX4 antioxidant defense, and TFEB-dependent lysosomal iron regulation; recent NCOA4 perturbation data also strengthen the ferritinophagy evidence. By contrast, P2X7, ATP-binding cassette transporter A1, microRNA-223, and cGAS-STING remain less uniformly validated, and direct acupuncture evidence for AIM2 signaling and necroptosis remains lacking. Clinical studies support acupuncture primarily as an adjunctive intervention for functional recovery and do not establish inflammasome activation, pyroptosis, ferroptosis, or other animal-defined molecular events as mediators of clinical benefit. Future studies should distinguish pretreatment from post-onset therapy, standardize acupoint and stimulation parameters, and combine cell-specific perturbation, time-resolved sampling, and clinically accessible intermediate phenotypes to determine whether experimentally defined mechanisms translate into neurological recovery.