Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy

Hepatocellular carcinoma is the most prevalent form of primary liver cancer with a multifactorial aetiology comprising genetic, environmental, and behavioural factors. Evading cell death is a defining hallmark of hepatocellular carcinoma, underpinning tumour growth, progression, and therapy resistance. Ferroptosis is a form of nonapoptotic cell death driven by an array of cellular events, including intracellular iron overload, free radical production, lipid peroxidation and activation of various cell death effectors, ultimately leading to rupture of the plasma membrane. Although induction of ferroptosis is an emerging strategy to suppress hepatocellular carcinoma, malignant cells manage to develop adaptive mechanisms, conferring resistance to ferroptosis and ferroptosis-inducing drugs. Herein, we aim at elucidating molecular mechanisms and signalling pathways involved in ferroptosis and offer our opinions on druggable targets and new therapeutic strategy in an attempt to restrain the growth and progression of hepatocellular carcinoma through induction of ferroptotic cell death.