Hexokinase 2 (HK2)是第一种糖酵解速率限制酶，与肿瘤发生和进展密切相关。急需能够针对HK2的有效治疗药物。伯根宁显示出各种药理活性，如抗肿瘤特性。然而，伯根宁对癌细胞异常葡萄糖代谢的影响尚不清楚。本研究中，发现HK2在OSCC组织中过度表达，而HK2的消耗则抑制了体外和体内的OSCC细胞生长。此外，这些结果显示，天然化合物伯根宁对OSCC细胞具有强大的抗肿瘤效应。伯根宁通过下调HK2，抑制了癌细胞增殖，抑制了糖酵解，并在OSCC细胞中诱导内生性凋亡。值得注意的是，伯根宁恢复了放射治疗对放射耐药性OSCC细胞的抗肿瘤功效。机械学研究揭示了伯根宁通过增强PTEN和UBP13的相互作用，稳定PTEN，上调PTEN蛋白水平，从而抑制了AKT磷酸化和HK2表达。伯根宁被鉴定为一种新型的抗糖酵解治疗药物，用于抑制OSCC并克服放射耐药性。针对PTEN / AKT / HK2信号通路可能是临床OSCC治疗的一个有前景的选择。

Hexokinase 2 (HK2), the first glycolytic rate-limiting enzyme, is closely correlated with the occurrence and progression of tumors. Effective therapeutic agents targeting HK2 are urgently needed. Bergenin has exhibited various pharmacological activities, such as antitumor properties. However, the effects of bergenin on the abnormal glucose metabolism of cancer cells are yet unclear. In this study, HK2 was overexpressed in OSCC tissues, and the depletion of HK2 inhibited the growth of OSCC cells in vitro and in vivo. Moreover, these results showed that the natural compound, bergenin, exerted a robust antitumor effect on OSCC cells. Bergenin inhibited cancer cell proliferation, suppressed glycolysis, and induced intrinsic apoptosis in OSCC cells by downregulating HK2. Notably, bergenin restored the antitumor efficacy of irradiation in the radioresistant OSCC cells. A mechanistic study revealed that bergenin upregulated the protein level of phosphatase and the tensin homolog deleted on chromosome 10 (PTEN) by enhancing the interaction between PTEN and ubiquitin-specific protease 13 (USP13) and stabilizing PTEN; this eventually inhibited AKT phosphorylation and HK2 expression. Bergenin was identified as a novel therapeutic agent against glycolysis to inhibit OSCC and overcome radioresistance. Targeting PTEN/AKT/HK2 signaling could be a promising option for clinical OSCC treatment.