RIPK3, or receptor-interacting protein kinase 3, is a serine/threonine-protein kinase. As a key part of necrosomes, it is essential for inflammatory factors (like TNFα) and infection-induced necroptosis, a form of programmed necrosis. RIPK3 is also involved in regulating apoptosis, cytokine/chemokine production, mitochondrial metabolism, autophagy, and cell proliferation by interacting with and phosphorylating critical signaling pathway regulators [1]. Genetic models, such as gene knockout mouse models, have been valuable in studying RIPK3.

In various disease models, RIPK3 has shown distinct roles. RIPK3-deficient mice are healthy, in contrast to RIPK1-deficient mice which die soon after birth. RIPK3 deficiency ameliorates various mouse disease models, suggesting necroptosis 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 NAFLD, Ripk3-deficient mice had rescued mitochondrial biogenesis, bioenergetics, and function, along with changes in lipid droplet dynamics [4].

In conclusion, RIPK3 plays crucial roles in necroptosis and multiple cellular processes. Studies using KO mouse models have revealed its significance in diseases like cardiac ischemia/reperfusion injury and NAFLD. Understanding RIPK3's functions through these models can potentially lead to new therapeutic strategies for related diseases.

References:

1. Liu, Shanhui, Joshi, Kanak, Denning, Mitchell F, Zhang, Jiwang. 2021. RIPK3 signaling and its role in the pathogenesis of cancers. In Cellular and molecular life sciences : CMLS, 78, 7199-7217. doi:10.1007/s00018-021-03947-y. https://pubmed.ncbi.nlm.nih.gov/34654937/

2. Newton, Kim. 2015. RIPK1 and RIPK3: critical regulators of inflammation and cell death. In Trends in cell biology, 25, 347-53. doi:10.1016/j.tcb.2015.01.001. https://pubmed.ncbi.nlm.nih.gov/25662614/

3. Zhang, Wenjia, Zhang, Junxia, Wang, Zeyuan, Zhang, Shuyang, Zhang, Yan. 2024. Extracellular RIPK3 Acts as a Damage-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury. In Circulation, 150, 1791-1811. doi:10.1161/CIRCULATIONAHA.123.068595. https://pubmed.ncbi.nlm.nih.gov/39411860/

4. Afonso, Marta B, Islam, Tawhidul, Magusto, Julie, Gautheron, Jérémie, Rodrigues, Cecília M P. 2022. RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease. In Hepatology (Baltimore, Md.), 77, 1319-1334. doi:10.1002/hep.32756. https://pubmed.ncbi.nlm.nih.gov/36029129/