Endometriosis is increasingly recognized as a chronic systemic disorder extending beyond the classical estrogen-dependent paradigm, integrating metabolic, immune, fibrotic, and nociceptive pathways that sustain lesion persistence and refractory pelvic pain. We propose a mechanistic, translational hypothesis in which tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, may modulate four interconnected pathological axes of refractory endometriosis-Warburg-type metabolic reprogramming with lactate accumulation, peritoneal immune dysfunction, NF-κB/NLRP3/TGF-β1-driven inflammatory-fibrotic remodeling, and persistent nociceptive sensitization-through three convergent molecular nodes: AMPK-associated signaling, GLP-1 receptor activity in peritoneal macrophages and spinal microglia, and the NF-κB/NLRP3/TGF-β1 axis. Particular emphasis is placed on the concept of "peritoneal incretin deficiency", characterized by reduced peritoneal GLP-1 concentrations and increased expression of incretin-degrading proteases. This concept currently rests on a single, non-replicated case-control study, and the broader mechanistic chain is supported largely by indirect evidence extrapolated from adjacent inflammatory, metabolic, and neuroimmune disease models rather than by endometriosis-specific data. Direct experimental or clinical validation in endometriosis-specific models is currently absent. Accordingly, this article represents a hypothesis-generating framework rather than evidence of established efficacy, or a clinical treatment recommendation, intended to guide future mechanistic and prospective clinical investigation of incretin-based modulation as a potential adjunctive strategy in refractory endometriosis.
