组蛋白乳酰化介导USP22/HIF-1α正反馈环路促进糖尿病视网膜病变的进展
Histone lactylation mediates the USP22/HIF-1α positive feedback loop to promote the progression of diabetic retinopathy.
摘要(中文译文)
本研究旨在探讨USP22在糖尿病视网膜病变(DR)中的作用及分子机制，重点关注组蛋白乳酸化对其的调控及其与HIF-1α形成的正反馈环路。通过腹腔注射STZ建立DR小鼠模型，并采用高糖(HG)处理ARPE-19和mRPE细胞构建体外DR模型。通过CCK-8、EdU染色等实验评估细胞损伤，通过H&E染色和TUNEL染色评估视网膜损伤。在体内和体外DR模型中，USP22表达均显著升高。敲低USP22可减轻DR小鼠的视网膜损伤，并减少HG暴露的ARPE-19和mRPE细胞损伤，该效应与糖酵解受抑制相关。HIF-1α在DR中亦上调。Co-IP实验证实USP22通过去泛素化稳定HIF-1α。过表达HIF-1α可部分逆转USP22敲低对HG条件下糖酵解和细胞损伤的抑制作用。此外，ChIP分析揭示糖酵解产物乳酸通过H3K18la修饰促进USP22转录和表达，形成糖酵解/H3K18la/USP22/HIF-1α正反馈环路。在HG暴露细胞中，过表达HIF-1α可逆转糖酵解抑制剂2-DG对USP22 H3K18la修饰及表达的抑制作用，同时减弱2-DG对细胞损伤的保护作用。与此一致，在体内，敲低USP22/HIF-1α或2-DG处理可下调DR视网膜中USP22、Pan Kla和H3K18la水平，同时改善视网膜结构损伤和凋亡。本研究揭示了DR中存在“糖酵解/H3K18la/USP22/HIF-1α”正反馈环路，促进疾病进展。
Abstract
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. 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. 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. Our study reveals that a "glycolysis/H3K18la/USP22/HIF-1α" positive feedback loop exists in DR, promoting disease progression.
如何引用
AMA
Hong Xu, Ling Wang, Yiyi Luo, Libo Zhang, Yepin Zhang, Peiqi Chen, et al. Histone lactylation mediates the USP22/HIF-1α positive feedback loop to promote the progression of diabetic retinopathy.. Biochimica et biophysica acta. Molecular basis of disease. 2027; doi:10.1016/j.bbadis.2026.168448.
APA
Hong Xu, Ling Wang, Yiyi Luo, Libo Zhang, Yepin Zhang, Peiqi Chen, et al (2027). Histone lactylation mediates the USP22/HIF-1α positive feedback loop to promote the progression of diabetic retinopathy.. Biochimica et biophysica acta. Molecular basis of disease. https://doi.org/10.1016/j.bbadis.2026.168448
GB/T 7714
Hong Xu, Ling Wang, Yiyi Luo, Libo Zhang, Yepin Zhang, Peiqi Chen, et al. Histone lactylation mediates the USP22/HIF-1α positive feedback loop to promote the progression of diabetic retinopathy.[J]. Biochimica et biophysica acta. Molecular basis of disease, 2027 doi:10.1016/j.bbadis.2026.168448.
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