南京医科大学姚兵研究小组开发出缺氧诱导因子-1α驱动癌症对铜增生的抵抗。这一研究成果于2025年3月6日发表在国际顶尖学术期刊《癌细胞》上。

本研究揭示了缺氧诱导因子-1α (HIF-1α)是实体瘤中铜增生抵抗的驱动因素。小组发现HIF-1α激活丙酮酸脱氢酶激酶1和3 (PDK1/3)，导致二氢脂酰胺s -乙酰转移酶（DLAT）（铜靶）的表达降低，并促进金属硫蛋白的积累，金属硫蛋白可以固载线粒体中的铜，从而在缺氧条件下抵抗铜还原。

此外，该研究团队发现高水平的铜可以减少泛素化，增加HIF-1α蛋白的稳定性，而不影响其mRNA水平。抑制HIF-1α增加体内癌症对铜变性的易感性。本研究揭示了HIF-1α在铜质增生中的多方面作用，并揭示了缺氧促进癌变的分子机制。

据了解，铜细胞凋亡是一种新型的细胞死亡，与铜稳态和蛋白质脂酰化密切相关。低氧肿瘤微环境（TME）是铜增生抑制的特征。

附：英文原文

Title: Hypoxia inducible factor-1α drives cancer resistance to cuproptosis

Author: Zhou Yang, Wei Su, Xiyi Wei, Yitong Pan, Mengying Xing, Lili Niu, Baijie Feng, Weiyu Kong, Xiaohan Ren, Feng Huang, Jingwan Zhou, Wei Zhao, Yingyi Qiu, Tian Liao, Qi Chen, Shuang Qu, Yunjun Wang, Qing Guan, Duanshu Li, Ke Zen, Yun Chen, Chao Qin, Yu Wang, Xiang Zhou, Jun Xiang, Bing Yao

Issue&Volume: 2025-03-06

Abstract: Cuproptosis represents a new type of cell death that intricately associated with copper homeostasis and protein lipoylation. The cuproptosis suppression has been characterized in the hypoxic tumor microenvironment (TME). Here we reveal that hypoxia inducible factor-1α (HIF-1α) is a driver of cuproptosis resistance in solid tumor. We found that HIF-1α activates pyruvate dehydrogenase kinase 1 and 3 (PDK1/3), resulting in decreased expression of dihydrolipoamide S-acetyltransferase (DLAT) (target of copper), and promotes the accumulation of metallothionein, which sequesters mitochondrial copper, leading to resistance to cuproptosis under hypoxic conditions. Furthermore, we discovered that high levels of copper reduce ubiquitination and increase the stability of HIF-1α protein without affecting its mRNA levels. Inhibition of HIF-1α increases the susceptibility of cancer to cuproptosis in vivo. This study unveils the multifaceted role of HIF-1α in cuproptosis and demonstrates the molecular mechanism of hypoxia-promoted carcinogenesis.

DOI: 10.1016/j.ccell.2025.02.015

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00067-4