Corneal Sensory Denervation Causes Epithelial Ferroptosis and Delayed Healing in Mice

This study aimed to elucidate the role and mechanism of corneal nerves in regulating epithelial cell response against ferroptosis.

Denervated mouse models were established via surgical axotomy and capsaicin treatment. Monochlorobimane staining was employed to detect cellular glutathione (GSH) levels in the corneal epithelium, and real-time quantitative PCR and immunofluorescence staining were used to evaluate GSH-related gene expression in denervated models and corneas of patients with neurotrophic keratitis. Scanning electron microscopy was utilized to observe mitochondrial morphology in corneal epithelial cells. Ferroptosis inhibitor ferrostatin-1 was administered post-corneal scrape in capsaicin-treated mice, followed by transcriptomic sequencing. The p53 agonist Kevetrin activated p53 in scraped corneas and cultured corneal epithelial cells. Furthermore, capsaicin was topically applied to Trp53+/- mice, followed by corneal epithelial scraping.

In denervated models, the expression of GSH-related genes was downregulated, and mitochondrial morphology exhibited characteristics of ferroptosis in corneal epithelial cells. The delay in corneal wound healing induced by TRPV1+ sensory denervation was ameliorated by ferrostatin-1 treatment. RNA sequencing and immunofluorescence staining demonstrated upregulated p53 in TRPV1-denervated mice, which was subsequently downregulated following ferrostatin-1 treatment. Kevetrin exacerbated wound healing delays, whereas Trp53+/- mice exhibited accelerated healing post-capsaicin denervation compared to wild-type controls.

TRPV1+ sensory nerves play a regulatory role in preventing ferroptosis of corneal epithelial cells through the p53/AKT/mTOR signaling pathway. Targeting this pathway may offer therapeutic potential for neurotrophic keratopathy and related disorders.