From benign liver disease to cancer: a matter of life and death

Chronic liver diseases represent an escalating global health burden, with metabolic dysfunction-associated steatotic liver disease (MASLD) emerging as a key driver of hepatocarcinogenesis. This seminar highlights the critical role of RIPK3, a central effector of necroptosis—a regulated, pro-inflammatory form of cell death—in liver disease progression. In MASLD, RIPK3 promotes hepatic inflammation, fibrosis, and tumorigenesis by inducing cell death and disrupting metabolic homeostasis, establishing it as both a pathological hallmark and a promising therapeutic target.

In turn, in established liver cancers such as cholangiocarcinoma, resistance to cell death within specific cell subpopulations remains a major therapeutic barrier. Preclinical evidence supports the induction of non-apoptotic, immunogenic forms of cell death—particularly ferroptosis—as a powerful strategy to eliminate these resilient tumor-initiating cells and exploit metabolic vulnerabilities in aggressive, treatment-refractory liver cancers.

Together, these insights unveil new avenues for reprogramming cell fate as a therapeutic strategy to halt chronic liver disease progression and combat liver cancer.