NLRP3/Caspase-1-Mediated Pyroptosis Drives a Brain-Lesion Neuroimmune Axis in Endometriosis-Associated Pain: Molecular Mechanisms and Transcranial Direct Current Stimulation Intervention.

Background/Objectives: The NLRP3 inflammasome-Caspase-1-IL-1β pyroptotic axis participates in peripheral inflammatory responses, yet its function in peripheral-central neuroimmune crosstalk underlying endometriosis (EM)-associated pain remains unclear. This study aimed to clarify whether NLRP3-mediated pyroptosis establishes a brain-lesion neuroimmune axis connecting ectopic lesion inflammation with central neuroimmune remodeling and to explore the therapeutic mechanism of transcranial direct current stimulation (tDCS). Methods: An EM rat model was established to detect NLRP3 pathway expression in ectopic lesions and anterior cingulate cortex (ACC), together with central nervous system pathological alterations. Animals received tDCS intervention to evaluate inflammatory, neuropathological and pain behavioral changes. The closed-loop brain-lesion regulatory circuit was further interpreted. In a clinical cohort including 40 EM patients, pain and quality-of-life scores were compared between active and sham tDCS groups. Results: NLRP3, Caspase-1 and IL-1β were upregulated in ectopic lesions and ACC of EM rats, accompanied by ACC mitochondrial injury, microglial activation and thalamic demyelination. tDCS inhibited pyroptosis-related molecules, decreased systemic proinflammatory cytokines, improved central pathological lesions and relieved pain hypersensitivity. Mechanically, top-down descending pain inhibitory pathways, vagal cholinergic anti-inflammatory pathway and the HPA axis jointly mediate therapeutic effects, whereas circulating cytokines and visceral afferents transmit peripheral inflammatory signals to the brain. Clinical data demonstrated that active tDCS effectively alleviated EM-related pain and improved patients' quality of life. Conclusions: NLRP3-mediated pyroptosis acts as a key mediator linking peripheral and central neuroimmune communication. Targeting this pathway via tDCS interrupts the inflammation-pain vicious cycle through multiple neuroregulatory pathways and remodels the central neuroimmune microenvironment in endometriosis.