Histone lactylation mediates the USP22/HIF-1α positive feedback loop to promote the progression of diabetic retinopathy.

OBJECTIVE: This study aims to investigate the role and molecular mechanism of USP22 in diabetic retinopathy (DR), focusing on its regulation by histone lactylation and a positive feedback loop with HIF-1α. METHODS: A DR mouse model was established via intraperitoneal injection of STZ, and in vitro DR models were induced using high glucose (HG) treatment in ARPE-19 and mRPE. Cell damage was assessed through CCK-8, EdU staining, and other experiments, while retinal damage was evaluated via H&E staining and TUNEL staining. RESULTS: In DR models both in vivo and in vitro, USP22 expression was significantly elevated. Knockdown of USP22 alleviated retinal damage in DR mice and reduced injury in ARPE-19 and mRPE cells exposed to HG, an effect associated with suppressed glycolysis. HIF-1α was also upregulated in DR. Co-IP assays confirmed that USP22 stabilizes HIF-1α through deubiquitination. Overexpression of HIF-1α partially reversed the inhibitory effects of USP22 knockdown on glycolysis and cellular damage under HG conditions. Furthermore, ChIP analysis revealed that lactate, a glycolytic product, promotes USP22 transcription and expression via H3K18la modification, forming a glycolysis/H3K18la/USP22/HIF-1α positive feedback loop. HIF-1α overexpression reversed the glycolysis inhibitor 2-DG-induced suppression of USP22 H3K18la modification and expression in HG-exposed cells, while attenuating the protective effect of 2-DG against cellular injury. Consistently, in vivo, knockdown of USP22/HIF-1α or 2-DG treatment downregulated USP22, Pan Kla, and H3K18la in DR retinas, while ameliorating retinal structural damage and apoptosis. CONCLUSION: Our study reveals that a "glycolysis/H3K18la/USP22/HIF-1α" positive feedback loop exists in DR, promoting disease progression.