RIPK3, short for receptor-interacting protein kinase 3, is a serine/threonine-protein kinase. As a key component of necrosomes, it is an essential mediator of inflammatory factors (such as TNFα) and infection-induced necroptosis, a form of programmed necrosis. RIPK3 signaling is also 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].

RIPK3-deficient mice have been used in multiple studies to reveal its functions. In metabolic liver disease, Ripk3 deficiency restored mitochondrial bioenergetics and affected lipid droplet dynamics in mice fed a CDAA diet, suggesting RIPK3 may play a role in NAFLD progression [3]. In cardiac ischemia/reperfusion injury, extracellular RIPK3 acts as a damage-associated molecular pattern to exaggerate injury, and in vivo mouse models confirmed that recombinant RIPK3 protein exacerbated injury while the RIPK3 antibody alleviated it [2]. In addition, in some cancers like pancreatic and colorectal cancers, RIPK3 signaling might promote cancer development, while in most cancers, its-mediated necroptosis is inactivated, potentially playing a suppressive role [1].

In conclusion, RIPK3 plays diverse and significant roles in various biological processes and diseases. Studies using RIPK3-deficient mouse models have helped to clarify its functions in areas such as metabolic liver disease, cardiac ischemia/reperfusion injury, and cancer pathogenesis. These findings provide potential therapeutic targets 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. 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/

3. 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/