Nociceptive Nerve‐Derived CGRP Exacerbates Uterine Fibrogenesis in Adenomyosis by Promoting CD140b ⁺ CD146 ⁺ Fibroblast Differentiation

Abstract Progressive dysmenorrhea and extensive fibrosis within the myometrium are hallmark features of adenomyosis (AM). Approximately 80% of patients with AM experience secondary dysmenorrhea, which occurs more frequently in AM than in other gynecological disorders. Because nociceptive nerves mediate dysmenorrhea, their contribution to AM‐associated fibrosis is investigated. These results demonstrate overexpression of calcitonin gene‐related peptide (CGRP)+ nociceptive nerves within fibrotic lesions in both AM patients and murine models; nociceptive nerve ablation reduces uterine fibrosis in mice with induced AM. CGRP, secreted by nociceptive nerves, drives receptor activity‐modifying protein 1 (RAMP1) high‐expressing (RAMP1 ^hi ) CD140b ⁺ CD146 ⁺ fibroblasts in AM lesions toward an extracellular matrix deposition subtype through activation of the extracellular signal‐regulated kinase pathway. Treatment of mice with AM using rimegepant, a United States Food and Drug Administration‐approved drug that blocks CGRP/RAMP1 signaling, alleviated progression of AM‐associated fibrosis and promoted fertility restoration. This study identifies a previously unrecognized nerve‐fibroblast crosstalk mechanism and provides a potential nonhormonal therapeutic strategy for AM treatment, particularly in women of reproductive age.