Topical NAMPT activation restores mitophagic flux to rescue diabetic keratopathy via the NAD⁺/PINK1 pathway.

BACKGROUND: Diabetic keratopathy (DK) is a sight-threatening complication affecting up to 70% of diabetic patients, for which there are currently no effective therapies to halt disease progression. This study seeks to identify a novel DK biomarker and characterize its mechanistic role in disease pathogenesis. METHODS: Proteomic analysis was performed on conjunctival epithelial cells from diabetic patients with and without DK using iTRAQ labeling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differential protein expression was validated in diabetic mouse models, human diabetic corneas, and high glucose-induced epithelial cell models. The role of nicotinamide phosphoribosyltransferase (NAMPT) in regulating mitophagy in corneal epithelial cells was further investigated through genetic manipulation. The protective effects of the NAMPT activator P7C3 on corneal nerves and epithelium were evaluated in db/db mice. RESULTS: NAMPT was identified as a differentially expressed protein. Chronic hyperglycemia selectively depleted mitochondrial NAMPT in corneal epithelial cells, disrupting nicotinamide adenine dinucleotide (NAD) biosynthesis and triggering a self-amplifying cycle of oxidative stress and impaired PINK1-mediated mitophagy, ultimately leading to apoptosis. In diabetic db/db mice, topical application of the NAMPT activator P7C3 enhanced NAMPT activity, restored mitochondrial quality control, attenuated epithelial degeneration, reduced stromal edema, restored tear secretion, and promoted regeneration of corneal nerves and epithelium. CONCLUSIONS: Mitochondrial localization of NAMPT expression loss is a central driver of DK pathogenesis. Topical application of the NAMPT activator P7C3 holds promise for restoring both corneal homeostasis and tear secretion function, making it a novel therapeutic target for oxidative stress-related corneal diseases and Diabetic Dry Eye Syndrome. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-026-02784-5.