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

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.

To investigate the function of PGRN in corneal repair under normal and diabetic conditions and to identify underlying mechanisms.

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.

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.

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.