Migraine-induced cochlear injury triggers ZBP1-mediated PANoptosis via CGRP signaling.

Abstract

OBJECTIVE: Consequences of hearing abnormalities in migraine remain largely unexplored, particularly regarding peripheral outcomes. This study aims to explore how migraine induces peripheral auditory injury and what role calcitonin gene-related peptide (CGRP) plays in the inner ear, which may contribute to the precise subtyping of migraine and inform targeted auditory-protective therapies. METHODS: A mouse model of chronic migraine (CM) was established by intermittent injections of nitroglycerin and validated via mechanical and thermal nociceptive assays. CGRP signaling was assessed by Western blotting and immunofluorescence. Auditory function was evaluated using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) in CM and CGRP blockade (Rimegepant-treated) groups. RNA sequencing of cochlear tissue identified dysregulated signaling pathways, which were subsequently validated in vitro using HEI-OC1 auditory cells and in vivo within the inner ear. RESULTS: Repeated nitroglycerin injections induced persistent mechanical and thermal hyperalgesia, confirming successful model establishment. A significant upregulation of CGRP and its receptors, particularly in outer hair cells (OHCs) were confirmed. The CM mouse exhibited elevated ABR, DPOAE thresholds and OHC injury, all of which were mitigated by Rimegepant treatment. CGRP overstimulation triggered mitochondrial stress and mtDNA leakage in HEI-OC1 cells. Cytosolic mtDNA leakage activated the ZBP1-mediated PANoptosis pathway, leading to OHC injury. As proof of concept, ZBP1 knockdown and PANoptosis inhibition mitigated cellular damage and hearing deficits both in vivo and in vitro. CONCLUSIONS: We demonstrated OHCs as the key targets in CM-induced, CGRP-mediated peripheral hearing impairment. CGRP exerts its pathogenic role by triggering a cascade of intracellular stress and inflammatory pathways, ultimately leading to cell death. These findings provide a phenotypic basis for a subtype of migraine-induced hearing loss, paving the way for auditory protection strategies.