Electroacupuncture protects gastric Cajal cells by reducing macrophage pyroptosis in diabetic gastroparesis

BACKGROUND This study elucidates the mechanisms through which electroacupuncture (EA) at Zusanli acupoint, applied at different frequencies, alleviates diabetic gastroparesis (DGP). The modulation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, its regulation of M2 macrophage pyroptosis, and the consequent protection of interstitial cells of Cajal (ICCs) were investigated. AIM To investigate the mechanism by which EA alleviates DGP. METHODS A DGP rat model was induced by feeding a high-fat/high-sucrose diet combined with a single intraperitoneal injection of streptozotocin (30 mg/kg). Rats successfully modeled were randomly assigned into four groups (n = 6 each): Untreated DGP, sham-EA (0 Hz, 0 mA), low-frequency EA (LEA, 10 Hz, 1-3 mA), and high-frequency EA (HEA, 100 Hz, 1-3 mA). EA was delivered at Zusanli acupoint for 60 minutes daily over 8 weeks. Gastric emptying rate and whole gut transit time were evaluated. Gastric antrum tissues were examined by immunofluorescence and western blotting to assess ICC integrity, M2 macrophage distribution, pyroptosis-related markers (Gasdermin D, NOD-like receptor family pyrin domain containing 3, caspase-1), inflammatory cytokines [interleukin (IL)-1β, IL-18], and cGAS-STING signaling proteins. RESULTS The results of this study revealed that HEA significantly increased gastric emptying [0.69 (0.55, 0.72) vs DGP 0.44 (0.26, 0.48), P < 0.05] and reduced whole gut transit time (361.34 ± 10.51 vs DGP 537.33 ± 100.57, P < 0.01), with improved efficacy compared to LEA. In DGP rats, ICC counts were significantly reduced, transferase dUTP nick-end labeling-positive apoptotic markers were elevated, and CD206+ cells were diminished; these alterations were reversed mainly by EA, with HEA showing the greatest effect. Expression of cGAS-STING signaling components and pyroptosis-related proteins (Gasdermin D, NOD-like receptor family pyrin domain containing 3, caspase-1), along with secretion of IL-1β and IL-18, were significantly up-regulated in the DGP group. HEA significantly suppressed cGAS pathway activation, reduced pyroptosis-associated proteins and inflammatory mediators, and outperformed LEA (P < 0.05). CONCLUSION HEA ameliorates gastric dysmotility in DGP by suppressing the cGAS-STING pathway, attenuating M2 macrophage pyroptosis and inflammatory responses, and preserving ICC networks. These findings identify a novel EA/cGAS-STING/pyroptosis axis and highlight its therapeutic potential as a mechanistic target for optimizing DGP treatment strategies.