Receptor-interacting protein kinase 3 (RIPK3) is a key component of necroptosis, a form of programmed cell death that does not rely on caspases. RIPK3 interacts with RIPK1 to form necrosomes, which trigger caspase-independent necroptosis. RIPK3 plays a crucial role in various pathological processes, including infections, inflammatory diseases, and tumors. It regulates autophagy, cell proliferation, and the production of chemokines/cytokines. The RIPK3 signaling pathway is involved in the pathogenesis of various cancers and exhibits both tumor-promoting and -suppressive activities. Recent studies have highlighted the potential of RIPK3 as a therapeutic target for treating diseases such as ischemic injury, inflammation, neurodegenerative disorders, and cancer. RIPK3 can be activated by various receptors, including death receptor ligands like TNF, FASLG, and TRAIL, and by Toll-like receptors (TLRs) and ZBP1. The activation of RIPK3 leads to the phosphorylation of MLKL, which triggers cell death. RIPK3 also regulates NF-κB signaling, induces inflammasome activation, and affects cell cycle progression, autophagy, and metabolism. In diseases involving RIPK3, such as ischemic injury, acute and chronic inflammation, neurodegenerative disorders, and cancer, targeting RIPK3 may provide novel therapeutic strategies.Receptor-interacting protein kinase 3 (RIPK3) is a key component of necroptosis, a form of programmed cell death that does not rely on caspases. RIPK3 interacts with RIPK1 to form necrosomes, which trigger caspase-independent necroptosis. RIPK3 plays a crucial role in various pathological processes, including infections, inflammatory diseases, and tumors. It regulates autophagy, cell proliferation, and the production of chemokines/cytokines. The RIPK3 signaling pathway is involved in the pathogenesis of various cancers and exhibits both tumor-promoting and -suppressive activities. Recent studies have highlighted the potential of RIPK3 as a therapeutic target for treating diseases such as ischemic injury, inflammation, neurodegenerative disorders, and cancer. RIPK3 can be activated by various receptors, including death receptor ligands like TNF, FASLG, and TRAIL, and by Toll-like receptors (TLRs) and ZBP1. The activation of RIPK3 leads to the phosphorylation of MLKL, which triggers cell death. RIPK3 also regulates NF-κB signaling, induces inflammasome activation, and affects cell cycle progression, autophagy, and metabolism. In diseases involving RIPK3, such as ischemic injury, acute and chronic inflammation, neurodegenerative disorders, and cancer, targeting RIPK3 may provide novel therapeutic strategies.