The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis PP6, a serine/threonine phosphatase, plays a critical role in TAK1 inhibitor (TAK1i)-induced PANoptosis, a form of innate immune inflammatory lytic cell death. A CRISPR screen identified PP6 components, particularly PPP6C and its regulatory subunits, as key regulators of TAK1i-induced cell death. Loss of PPP6C significantly reduced TAK1i-induced PANoptosis, while combined depletion of PPP6R1, PPP6R2, and PPP6R3 was required to block cell death. Mechanistically, PP6 components promoted pro-death S166 auto-phosphorylation of RIPK1 and reduced pro-survival S321 phosphorylation, tipping the balance toward RIPK1-dependent PANoptosis. These findings highlight the importance of the PP6 complex in TAK1i-induced PANoptosis and suggest that targeting PP6 could be a therapeutic strategy for inflammatory conditions. PP6 also regulates innate immune responses by modulating TAK1 activation, cGAS-STING pathway, and NF-κB signaling. The study underscores the need for further research into phosphatases that negatively regulate inhibitory phosphorylation sites on RIPK1, which could be targeted for therapeutic modulation of RIPK1 signaling in inflammatory diseases.The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis PP6, a serine/threonine phosphatase, plays a critical role in TAK1 inhibitor (TAK1i)-induced PANoptosis, a form of innate immune inflammatory lytic cell death. A CRISPR screen identified PP6 components, particularly PPP6C and its regulatory subunits, as key regulators of TAK1i-induced cell death. Loss of PPP6C significantly reduced TAK1i-induced PANoptosis, while combined depletion of PPP6R1, PPP6R2, and PPP6R3 was required to block cell death. Mechanistically, PP6 components promoted pro-death S166 auto-phosphorylation of RIPK1 and reduced pro-survival S321 phosphorylation, tipping the balance toward RIPK1-dependent PANoptosis. These findings highlight the importance of the PP6 complex in TAK1i-induced PANoptosis and suggest that targeting PP6 could be a therapeutic strategy for inflammatory conditions. PP6 also regulates innate immune responses by modulating TAK1 activation, cGAS-STING pathway, and NF-κB signaling. The study underscores the need for further research into phosphatases that negatively regulate inhibitory phosphorylation sites on RIPK1, which could be targeted for therapeutic modulation of RIPK1 signaling in inflammatory diseases.