Integrative perspectives on electroacupuncture modulation of vagal–cholinergic and neuro–immune–metabolic regulation in long COVID

Long COVID is increasingly recognized as a multisystem condition involving persistent inflammation, autonomic dysregulation, and metabolic disturbance. The vagus nerve–mediated cholinergic anti-inflammatory pathway (CAP) provides a biologically plausible link between neural regulation and immune homeostasis, while metabolic pathways involving AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are closely related to mitochondrial function and energy balance. In this review, we synthesize evidence from neuroscience, immunology, and metabolic research to investigate how electroacupuncture (EA) may modulate vagal-cholinergic signaling and the downstream inflammatory and metabolic processes associated with long COVID. Experimental studies indicate that EA can influence CAP-related mechanisms, including α7 nicotinic acetylcholine receptor (α7nAChR)-mediated inhibition of NF-κB/NLRP3-related inflammatory signaling, and may also regulate AMPK–SIRT1–PGC-1α-associated metabolic pathways. Although clinical evidence is more indirect, it suggests that electroacupuncture may affect autonomic function, inflammatory markers, symptom burden, and neurophysiological regulation. To support a balanced interpretation, we organize the evidence in this review into a framework based on levels of evidence, which distinguishes direct preclinical findings from indirect clinical indicators and associations used to generate hypotheses. This framework highlights the potential convergence of vagal–cholinergic anti-inflammatory regulation and metabolic recovery pathways, while recognizing that several proposed connections—particularly those linking CAP-related signaling to improvements in long COVID symptoms—require further validation. Overall, this review provides a structured basis for future mechanistic studies and phenotype-oriented clinical trials evaluating EA as a neuromodulatory strategy for long COVID and related chronic inflammatory conditions.