Electroacupuncture Targeting the NLRP3 Inflammasome in Senescence‑associated Cognitive Impairment: Mechanistic Synthesis and Meta‑analysis of Clinical Randomized Controlled Trials

Abstract

Global population aging leads to a growing clinical demand for interventions against age-related cognitive decline (ARCD), including mild cognitive impairment (MCI, termed senescence-associated cognitive impairment [SACI] in this review)—a prodromal pathological stage preceding Alzheimer’s disease (AD) and vascular dementia. Chronic microglia-mediated neuroinflammation, predominantly triggered by excessive NLRP3 inflammasome activation, acts as a key upstream mediator of hippocampal neuronal injury and gradual cognitive decline in preclinical aging models.

Manual acupuncture and electroacupuncture (EA) exert reproducible neuroprotective effects against cognitive deficits, yet a comprehensive, multi-layered regulatory framework unifying NLRP3-centered molecular mechanisms of acupuncture remains absent from current literature. This review systematically summarizes NLRP3‑dependent pathological cascades in SACI and outlines four synergistic signaling axes through which acupuncture may modulate excessive NLRP3‑dependent inflammatory responses to potentially alleviate neurotoxic inflammatory injury.

Persistent overactivation of the NLRP3 inflammasome triggers self-amplifying inflammatory feedback cycles in hippocampal tissue through four interrelated pathological processes: impaired autophagic clearance, disrupted mitochondrial homeostasis, persistent endoplasmic reticulum (ER) stress, and caspase-1/GSDMD-mediated neuronal pyroptosis.

Acupuncture counteracts NLRP3-dependent neural injury through synergistic multi-target modulation: (1) activation of AMPK/mTOR signaling to restore defective autophagy; (2) suppression of the ROS-TXNIP cascade to block NLRP3 transcriptional priming and protein oligomerization; (3) phenotypic reprogramming of microglia from pro-inflammatory M1 toward anti-inflammatory M2 states; (4) inhibition of pyroptotic execution by blunting caspase-1 maturation and GSDMD proteolytic cleavage. Collectively, available pre‑clinical evidence suggests these signaling axes constitute a bidirectionally‑interconnected hypothetical protective network that may mitigate chronic neuroinflammation.

A meta analysis integrating nine eligible randomized controlled trials (published 2015–2025) involving 614 participants was performed. After subject dropout, 599 participants completed the studies. Pooled analyses of heterogeneous acupuncture/electroacupuncture RCTs revealed that intervention was associated with short‑term improvements in MoCA and MMSE scores and reduction in peripheral pro‑inflammatory cytokine IL‑6. Pooled effect sizes were moderately larger in MCI subgroups compared with patients with early AD. Nevertheless, substantial methodological heterogeneity existed across included trials, and these short term observational findings cannot confirm durable disease modifying benefits.

Severe methodological heterogeneity across existing trials—including inconsistent acupoint prescriptions, divergent EA stimulation parameters, and variable treatment cycles—impairs cross-study comparability and translational reproducibility. Herein, we synthesize high‑quality preclinical and clinical evidence to propose a provisional consensus‑oriented translational reference protocol for electroacupuncture, intended for standardized mechanistic research rather than routine clinical intervention.

Collectively, the NLRP3 inflammasome constitutes a tractable therapeutic target for acupuncture-mediated SACI intervention. Acupuncture exerts pleiotropic neuroprotection by dampening NLRP3-dependent neuroinflammation, alongside complementary NLRP3-independent regulatory pathways. This review‑meta‑analysis provides preliminary translational theoretical evidence for a provisional electroacupuncture intervention framework targeting NLRP3‑mediated neuroinflammation in MCI and early‑AD. Future high‑quality, multi‑center RCTs are warranted to validate these preliminary findings.