Linking necroptosis with liver aging and chronic inflammation in hepatic pathology

Necroptosis, a regulated form of cell death distinct from apoptosis and necrosis, is increasingly recognized for its role in chronic inflammation and tissue damage within the liver. It is mainly associated with upregulation of necroptotic factors like phosphorylated MLKL (Mixed lineage kinase domain-like protein), Receptor Interacting Kinase 1 (RIPK1), and Receptor Interacting Kinase 3 (RIPK3). The regulation of necroptotic signaling becomes increasingly impaired as liver age progresses, promoting a pro-inflammatory hepatic environment that contributes to the onset and development of age-related liver pathologies such as steatosis, fibrosis, and hepatocellular carcinoma (HCC). The chronic low-grade inflammation associated with aging, often termed "inflammaging," further amplifies necroptosis-mediated damage, establishing a vicious cycle of cell death and inflammatory signaling. Thus, understanding the mechanisms of necroptosis in the aging liver highlights new potential therapeutic targets to alleviate liver diseases. Current therapeutic strategies include the development of small molecule inhibitors that target crucial components of the necroptotic pathway, such as inhibitors of RIPK1 (e.g., Necrostatin-1), RIPK3, and MLKL blockers. The present review delves into the complex role of necroptosis in liver aging and chronic liver diseases, detailing the underlying mechanisms and the latest treatment approaches, and underscores the critical need for extensive research in the area.