Protective effects of pituitary adenylate cyclase-activating peptide (PACAP) on high glucose-induced damage in human corneal epithelial cell.

BACKGROUND: Diabetic keratopathy (DK), a vision-threatening complication of diabetes mellitus, remains a significant clinical challenge. Pituitaries adenylate cyclase-activating peptide 38 (PACAP38) has been demonstrated to have neuroprotective effects. This study aimed to investigate whether PACAP38 mitigates high glucose (HG)-induced damage in human corneal epithelial cells (HCECs) and to elucidate the underlying mechanisms. METHODS: HCECs were exposed to HG to simulate diabetic injury. Cell viability, apoptosis, migration, and autophagy were evaluated using Cell Counting Kit-8 (CCK-8), flow cytometry, Transwell assays, and Western blotting, respectively. RESULTS: Compared to the normal control (NC) group, HG significantly suppressed cell proliferation (p < 0.01), whereas PACAP38 treatment restored proliferative capacity (p < 0.01). PACAP38 enhanced cell migration, counteracting HG-induced impairment. At the molecular level, HG downregulated Ki-67 and Bcl-2 mRNA expression, while PACAP38 markedly upregulated these markers (p < 0.01). Notably, the HG impaired the autophagy in HCEC cells, while the PACAP38 significantly increased the autophagic ability. Mechanistically, PACAP38 increased the expression of p-AMPK, p-ERK, and Bcl-2 while reducing p62 (p < 0.01). Crucially, these protective effects were abolished by the autophagy inhibitor 3-MA or the AMPK inhibitor compound C (p < 0.05), confirming pathway dependency. CONCLUSIONS: Our findings demonstrate that HG compromises HCEC proliferation and migration while promoting apoptosis. PACAP38 counteracts these detrimental effects by activating AMPK/ERK signaling, thereby enhancing cell survival and autophagy under hyperglycemic conditions. These results highlight PACAP38 as a promising therapeutic candidate for diabetic keratopathy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12886-025-04309-z.