Corneal Sensory Denervation Causes Epithelial Ferroptosis and Delayed Healing in Mice

  • Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):28. doi: 10.1167/iovs.66.6.28.
Ning Wang  1  2 ,  Yizhou Li  2 ,  Xiaolei Wang  2 ,  Lingling Yang  2 ,  Jing Zhang  1  2 ,  Jun Cheng  1  2 ,  Xiaoyue Jiang  2  3 ,  Xia Qi  2 ,  Chao Wei  2 ,  Qingjun Zhou  2 ,  Ya Li  2 ,  Suxia Li  2  3
Affiliations
  • 1. Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.
  • 2. State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.
  • 3. Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, China.
PMID: 40488714 DOI: 10.1167/iovs.66.6.28
Abstract

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

Methods: 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.

Results: 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.

Conclusions: 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.

Products