Rethinking the role of HIF in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies worldwide, largely due to late diagnosis and limited therapeutic options. Tumor hypoxia is a hallmark of HCC and drives aggressive disease behavior, in part through activation of hypoxia‐inducible factors (HIFs). While HIF‐1α is classically understood as a hypoxia‐responsive transcription factor, its role under normoxic conditions in cells is less clear. The study presented by Gkotinakou and colleagues in this issue provides important insight into this question by revealing a previously underappreciated dependence of HIF‐1 signaling in controlling cell cycle progression in HCC, even in the presence of normal oxygen levels.