Jiang Dan, Sun Yining, Yu Xintong, Wang Ruoqi, Zhang Yuting, Yu Jinjie, Xie Shuang, Cai Yujia, Luo Yuhong, Chen Wei
National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
Adv Sci (Weinh). 2025 Sep;12(34):e03690. doi: 10.1002/advs.202503690. Epub 2025 Jun 20.
Herpes simplex keratitis (HSK) is a leading infectious cause of blindness worldwide, with current therapies primarily targeting viral replication rather than addressing host-cell injury. RNA sequencing of corneal tissue from HSK patients and healthy donors identifies a metabolic shift from mitochondrial oxidative phosphorylation to aerobic glycolysis. Notably, hexokinase-2 (HK2), a pivotal glycolytic enzyme, exhibits the greatest up-regulation, coinciding with a marked reduction in the activity of mitochondrial respiratory chain complexes in HSK corneas. Pharmacological inhibition of HK2 with lonidamine in human corneal epithelial cells reduces herpes simplex virus type 1 (HSV-1) replication while preserving cell viability. In a murine model of HSK, topical lonidamine restored respiratory-chain activity, lowered viral load, and accelerated corneal re-epithelialization; its early therapeutic efficacy surpassed that of ganciclovir, and combination therapy conferred additive benefit. These findings identify HK2-driven glycolytic reprogramming as a pathogenic hallmark of HSK and demonstrate that metabolic targeting concurrently restricts viral propagation and promotes tissue regeneration. Thus, metabolic intervention has the potential to complement direct antiviral therapy and represents a promising, clinically translatable strategy to preserve vision in HSK.
单纯疱疹病毒性角膜炎（HSK）是全球主要的感染性致盲原因，目前的治疗方法主要针对病毒复制，而非解决宿主细胞损伤问题。对HSK患者和健康供体的角膜组织进行RNA测序发现，其代谢从线粒体氧化磷酸化转变为有氧糖酵解。值得注意的是，关键的糖酵解酶己糖激酶-2（HK2）上调最为显著，这与HSK角膜中线粒体呼吸链复合物活性的显著降低相一致。在人角膜上皮细胞中用氯硝柳胺对HK2进行药理抑制可减少1型单纯疱疹病毒（HSV-1）的复制，同时保持细胞活力。在HSK小鼠模型中，局部应用氯硝柳胺可恢复呼吸链活性，降低病毒载量，并加速角膜再上皮化；其早期治疗效果优于更昔洛韦，联合治疗具有累加益处。这些发现确定HK2驱动的糖酵解重编程是HSK的致病标志，并表明代谢靶向可同时限制病毒传播并促进组织再生。因此，代谢干预有可能补充直接抗病毒治疗，并代表一种有前景的、可临床转化的策略，以保护HSK患者的视力。
