Ripk3, short for receptor-interacting protein kinase 3, is a serine/threonine-protein kinase. It is a key component of necrosomes and an essential mediator of inflammatory factors (e.g., TNFα) and infection-induced necroptosis, a form of programmed necrosis. Additionally, Ripk3 signaling is involved in regulating apoptosis, cytokine/chemokine production, mitochondrial metabolism, autophagy, and cell proliferation by interacting with and phosphorylating critical regulators of corresponding signaling pathways [1]. Genetic models, such as gene knockout (KO) mouse models, have been crucial in understanding its functions.

Ripk3-deficient mice are healthy, in contrast to RIPK1-deficient mice which die soon after birth [2]. In various disease models, Ripk3 deficiency has shown to ameliorate the pathology, suggesting that necroptosis mediated by Ripk3 contributes to the disease process. For example, in cardiac ischemia/reperfusion (I/R) injury, extracellular Ripk3 acts as a damage-associated molecular pattern to exaggerate the injury, and blocking it with an antibody alleviates the detrimental effects [3]. In metabolic liver disease, Ripk3 deficiency restores mitochondrial bioenergetics and impacts lipid droplet dynamics, showing promise in ameliorating non-alcoholic fatty liver disease (NAFLD) [4].

In conclusion, Ripk3 plays essential roles in multiple biological processes, especially in necroptosis. KO mouse models have been instrumental in revealing its roles in diseases like cardiac I/R injury and NAFLD. Understanding Ripk3's functions can potentially provide new therapeutic targets for these and other related diseases.