The RIP3 activator C8 regulates the autophagy flux mediated by p62 and promotes the immunogenic form of cell death in human gastric cancer cells.

There has been growing interest in investigating anti-tumor drugs that not only kill cancer cells but also stimulate the immune system, among them, necroptosis is a classical immunogenic form of cell death. In our study, we discovered that by targeting RIP3, Jaspine B derivative C8 induces necroptosis and initiates cell death, and this effect can be reversed by knockout of RIP3. Furthermore, RIP3 initiates autophagy and binds to p62 to inhibit autophagic flux. Additionally, the autophagy process mediated by RIP3 activates the Nrf2 signaling pathway via the formation of the p62/Keap1 complex. Early autophagy inhibitors enhance necroptosis by impending the accumulation of p62 and restraining the activation of Nrf2, whereas late autophagy inhibitors partially prevent C8-induced necroptosis. Notably, the immunogenic form of cell death induced by C8 did not affect tumor immunity. Overall, C8 functions as a RIP3 activator to suppress the development of gastric cancer. Upon activation, RIP3 regulates p62-mediated autophagic flux and the Nrf2 signaling pathway through the RIP3/p62/Keap1 axis.