Ferroptosis in liver fibrosis and its potential intervention strategy

Liver fibrosis, a common manifestation in numerous hepatic diseases, is critical in the progression from mild injury to cirrhosis and ultimately to hepatocellular carcinoma. To date, there are no effective pharmacological therapies for liver fibrosis. Ferroptosis is a type of programmed cell death characterized by alterations in redox lipid metabolism and is associated with the pathological conditions in liver fibrosis. The induction of ferroptosis is considered a novel way to kill hepatic stellate cells (HSCs). However, some studies in recent years challenge the existing paradigm. In addition to promoting HSC death, ferroptosis sets in motion the activation of profibrogenic HSCs and causes the death of hepatocytes and immune cells. In this review, we discuss the dual role of ferroptosis in promoting and inhibiting fibrosis in the liver, and the ferroptosis-related mechanisms underlying liver fibrosis of distinct etiologies. Despite significant progress in understanding ferroptosis's pathological roles in liver fibrosis, we highlight several critical questions that need to be addressed for strategies based on ferroptosis-targeted therapies, taking into account its ambiguous role in liver fibrosis.