Abstract
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.