Abstract

Background The transient receptor potential vanilloid 1 (TRPV1) is a cation channel implicated in neurological disorders. Although TRPV1 activation contributes to intracerebral hemorrhage (ICH) pathology, its microglia-specific role and underlying mechanisms remain poorly defined. This study investigates how microglial TRPV1 influences ICH injury. Methods We utilized a mouse ICH model alongside microglia-specific TRPV1 knockout mice, BV2 cells, and primary microglial cultures. Interventions included TRPV1 antagonist capsazepine (CPZ), agonist capsaicin (CAP), microglial depletion agent PLX5622, and TRPV1 knockdown. Outcomes were assessed using immunofluorescence, behavioral tests, Western blot, magnetic resonance imaging (MRI), and transmission electron microscopy (TEM). Results TRPV1 expression was significantly upregulated post-ICH, primarily in microglia. TRPV1 blockade with CPZ treatment reduced hematoma volume, brain edema, neuronal apoptosis, and improved neurological function, whereas CAP exacerbated injury. These benefits were replicated in microglia-specific TRPV1 knockout mice. Mechanistically, CPZ shifted microglia from a pro-inflammatory (iNOS+) to a regulatory (Arg1+) phenotype and suppressed excessive mitophagy via the Ca 2+ -AMPK-PINK1 pathway. Conclusion TRPV1 activation in microglia exacerbates ICH injury by promoting inflammation and disruptive mitophagy. Targeted inhibition of microglial TRPV1 represents a promising therapeutic strategy for ICH.