Letter to the Editor: From acupoint stimulation to immunometabolic regulation: What does electroacupuncture frequency really encode in diabetic gastroparesis?

Abstract

This letter builds on a recent study by Fan et al, demonstrating that electroacupuncture (EA) at the Zusanli acupoint can alleviate diabetic gastroparesis by suppressing macrophage pyroptosis via cyclic GMP-AMP synthase-stimulator of interferon genes pathway inhibition. While the authors convincingly demonstrated an immune-inflammatory mechanism underlying the therapeutic effects of EA, we argue that the most important implication of this work lies in how stimulation frequency may encode biologically distinct neuromodulatory information. In this view, EA is not merely a nonspecific peripheral intervention. We propose a hypothesis-driven, non-exclusive framework in which high-frequency EA preferentially engages afferent sensory fibers and autonomic neural circuits, thereby reshaping gastric immune tone and inflammatory thresholds in the diabetic state. Local tissue activation and vascular or perfusion-related dynamics may also operate in parallel. From this perspective, attenuation of macrophage pyroptosis and downstream cyclic GMP-AMP synthase-stimulator of interferon genes signaling can be viewed as secondary consequences of broader neuroimmune and immunometabolic reprogramming initiated by frequency-dependent neural inputs. Recognizing stimulation frequency as an informational variable rather than as a simple intensity parameter offers a rational framework for optimizing EA protocols, improving reproducibility, and extending neuromodulation-based strategies to other diabetes-associated complications characterized by immune and metabolic dysregulation.

Key Words: Electroacupuncture frequency; Neuromodulation; Diabetic gastroparesis; Neuroimmune interaction; Immunometabolic regulation

Core Tip: Electroacupuncture (EA) exerts therapeutic effects beyond local acupoint stimulation. This letter proposes that stimulation frequency encodes distinct neuromodulatory information that reshapes neuroimmune and immunometabolic regulation in diabetic gastroparesis. By reframing high-frequency EA as a frequency-encoded neuromodulatory strategy rather than a nonspecific peripheral intervention, we highlight how neural signaling may secondarily attenuate inflammatory pathways such as macrophage pyroptosis. This conceptual framework bridges traditional acupuncture with modern neuromodulation science and offers a rational basis for optimizing EA protocols in diabetes-associated gastrointestinal dysfunction. Importantly, this neuromodulatory interpretation is hypothesis-generating and intended to complement, rather than replace, other plausible mechanisms, including local tissue activation and perfusion-related effects.

TO THE EDITOR

Diabetic gastroparesis (DGP) is a challenging complication of diabetes characterized by impaired gastric motility, chronic inflammation, and limited therapeutic options. A recent study by Fan et al[1] demonstrated that electroacupuncture (EA) at the Zusanli acupoint significantly ameliorated DGP in a frequency-dependent manner, with high-frequency stimulation outperforming low-frequency stimulation. By linking EA treatment to suppression of macrophage pyroptosis through inhibition of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, the authors provided important mechanistic insights into how a nonpharmacological intervention can modulate immunoinflammatory processes in diabetic gastrointestinal dysfunction.

Beyond these valuable molecular observations, we believe that the most underappreciated implications of this work lie in the identification of a specific immune pathway and in the demonstration that EA frequency itself functions as a biologically meaningful signal. Rather than acting as a nonspecific peripheral stimulus, EA appears to encode distinct neuromodulatory information that shapes downstream immune and metabolic responses[1]. We do not infer frequency-encoded neuromodulation to be an exclusive explanatory mechanism. Rather, neural signaling may interact with frequency-dependent local tissue responses and vascular or perfusion-related dynamics to shape the observed immunometabolic phenotype. This perspective invites broad reconsideration of how EA exerts therapeutic effects on diabetes-associated disorders[1].

EA FREQUENCY AS A NEUROMODULATORY SIGNAL

EA is often discussed in terms of stimulation intensity or acupoint specificity[2-4]. However, electrical stimulation frequency may represent a more critical determinant of its biological effects[1,4]. The superior efficacy of high-frequency EA observed by Fan et al[1] cannot be adequately explained by stronger local stimulation alone. Instead, accumulating neurophysiological evidence suggests that different stimulation frequencies preferentially recruit distinct afferent sensory fibers and central neural circuits, resulting in divergent autonomic and neuroimmune outputs[5-7]. In parallel, frequency-dependent stimulation may also differentially activate local sensory endings and resident cellular components in the acupoint microenvironment, such as mast and stromal cells[5,6]. These effects may synergize with neural pathways rather than represent competing mechanisms.

This viewpoint sees EA as a frequency-encoded neuromodulatory intervention rather than as a uniform mechanical input. Frequency is an informational variable that shapes the interpretation and integration of peripheral nervous system stimulation. Consequently, the therapeutic advantage of high-frequency EA in DGP may reflect more effective engagement of neural pathways capable of recalibrating inflammatory thresholds and tissue homeostasis[1]. This interpretation reframes EA as a modality capable of delivering structured neural signals with systemic consequences.

FROM NEUROMODULATION TO IMMUNOMETABOLIC REGULATION

Reinterpretation of EA as neuromodulatory provides a coherent framework for understanding the immunological changes reported in this study. Suppression of macrophage pyroptosis and attenuation of cyclic GMP-AMP synthase-stimulator of interferon genes signaling may represent the downstream effects of broader neuroimmune reprogramming rather than direct cellular targeting by acupuncture[8]. Neural circuits engaged in frequency-specific EA can influence the local immune tone by modulating autonomic balance, vascular perfusion, and inflammatory set points within the gastric microenvironment.

In diabetes, chronic low-grade inflammation and immune dysregulation are systemic, rather than isolated gastric phenomena[9,10]. At the cellular level, this system of regulation is biologically plausible, as autonomic neural outputs can influence macrophage metabolic programming, mitochondrial stress, and redox balance. In addition, perfusion-dependent oxygen and nutrient availability can critically shape inflammatory thresholds and tissue repair capacity. Thus, the observed preservation of interstitial cells of Cajal and improvement in gastric motility may emerge from coordinated neuroimmune adjustments initiated by frequency-dependent neural inputs[11]. This system-level interpretation integrates neural signaling with immunometabolic regulation and avoids reducing EA efficacy to a single molecular pathway. It also helps explain why differences in stimulation parameters can yield markedly divergent biological and clinical outcomes.

TRANSLATIONAL IMPLICATIONS AND FUTURE DIRECTIONS

Recognizing EA frequency as a biologically meaningful signal raises important translational implications. Future studies should move beyond binary comparisons of EA vs no EA and systematically investigate how frequency encoding shapes neural, immune, and metabolic responses in diabetes[12-15]. This approach may improve reproducibility across studies and guide rational optimization of EA protocols for gastrointestinal dysfunction. Experimental validation of this hypothesis-driven framework will likely require integrative study designs that combine neural activity mapping, vascular or perfusion assessment, and immunometabolic profiling across stimulation frequencies.

Beyond DGP, this conceptual framework may have broader relevance to other diabetes-associated complications characterized by immunometabolic imbalance, including nephropathy, cardiomyopathy, and peripheral neuropathy[16]. These conditions share common features, including macrophage activation, inflammasome signaling, and impaired tissue repair. Although speculative, it is conceivable that frequency-encoded neuromodulation influences inflammatory thresholds across multiple organ systems. Importantly, this extrapolation should be viewed as a conceptual hypothesis rather than a direct therapeutic claim, warranting cautious organ-specific investigation.

In summary, Fan et al[1] highlight both a novel immune mechanism and a deeper principle on EA frequency that encodes neuromodulatory information capable of reshaping immunometabolic homeostasis in diabetes. Investigating this perspective may help redefine the study and translation of nonpharmacological neuromodulation for diabetic complications.