Ripk3, or 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 (like 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 through interactions with and phosphorylation of critical signaling pathway regulators [1].

Ripk3-deficient mice are healthy, while Ripk1-deficient mice die soon after birth. Various mouse models of disease are ameliorated by Ripk3 deficiency, suggesting that necroptosis mediated by Ripk3 contributes to pathology [2]. In cardiac ischemia/reperfusion injury, extracellular Ripk3 acts as a damage-associated molecular pattern to exaggerate injury, as shown in in vivo mouse models [3]. In metabolic liver disease, Ripk3 deficiency in mice fed a CDAA diet rescued mitochondrial function impairments and affected lipid droplet dynamics [4]. In hepatocarcinogenesis, Ripk3 down-regulation in tumor-associated macrophages correlated with tumorigenesis and M2 polarization in mouse models [5]. In IDH-mutated AML cells, the loss of Ripk3 protected cells from R-2HG-induced necroptosis [6]. In diabetic podocytopathy, Ripk3 knockout in mice improved albuminuria, podocyte loss, and renal ultrastructure [7].

In conclusion, Ripk3 plays crucial roles in multiple biological processes, especially in necroptosis and related cellular functions. Gene knockout mouse models have revealed its significant contributions to diseases such as cardiac ischemia/reperfusion injury, metabolic liver disease, hepatocarcinogenesis, AML, and diabetic podocytopathy, providing valuable insights into disease mechanisms and potential therapeutic targets.