Mediators of necroptosis: from cell death to metabolic regulation

Necroptosis, a programmed cell death mechanism distinct from apoptosis, has garnered attention for its role in various pathological conditions. While initially recognized for its involvement in cell death, recent research has revealed that key necroptotic mediators, including receptor-interacting protein kinases (RIPKs) and mixed lineage kinase domain-like protein (MLKL), possess additional functions that go beyond inducing cell demise. These functions encompass influencing critical aspects of metabolic regulation, such as energy metabolism, glucose homeostasis, and lipid metabolism. Dysregulated necroptosis has been implicated in metabolic diseases, including obesity, diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), contributing to chronic inflammation and tissue damage. This review provides insight into the multifaceted role of necroptosis, encompassing both cell death and these extra-necroptotic functions, in the context of metabolic diseases. Understanding this intricate interplay is crucial for developing targeted therapeutic strategies in diseases that currently lack effective treatments.