Hypoxia inducible factor-1α drives cancer resistance to cuproptosis.

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.