Progranulin restores diabetic corneal healing by modulating NF-κB-Driven inflammation and neuro-regenerative pathways.

Abstract

BACKGROUND: Diabetic keratopathy is characterized by delayed epithelial healing and reduced corneal nerve density, however effective treatment remains a significant challenge. Progranulin (PGRN), a secreted anti-inflammatory and neuroprotective factor, has been implicated in ocular homeostasis, but its role in the cornea has not been well defined. OBJECTIVE: To investigate the function of PGRN in corneal repair under normal and diabetic conditions and to identify underlying mechanisms. METHODS: PGRN expression in normal and diabetic mouse corneas was assessed by Western blot, ELISA, and immunohistochemistry. Corneal epithelial debridement models were established in normoglycemic, diabetic, and GRN-KO mice, followed by topical PGRN treatment. Epithelial healing and nerve regeneration were evaluated. In addition, inflammatory cytokines, neurotrophic factors, and transcriptomic changes were assessed in GRN-KO mice. RESULTS: PGRN was found significantly reduced in diabetic corneas, and topical exogenous PGRN accelerated epithelial closure and nerve regrowth in normal and diabetic mice. GRN-KO mice exhibited delayed healing and impaired nerve regeneration after wounding. RNA-seq revealed enrichment of neuroinflammation related pathways. GRN-KO corneas showed increased NF-κB activation and elevated IL-1β, IL-6, and TNF-α levels, whereas PGRN supplementation suppressed these inflammatory responses and enhanced IL-10, Arg-1, and NGF expression. CONCLUSION: PGRN is essential for maintaining corneal epithelial-neural-immune homeostasis. Its deficiency reproduces key features of diabetic keratopathy, while exogenous PGRN promotes repair and reduces neuroinflammation, supporting its potential as a therapeutic target.