The study investigates the role of protein phosphatase 6 (PP6) in TAK1-induced PANoptosis, a form of innate immune inflammatory lytic cell death. Through a CRISPR screen, the authors identified PP6 holoenzyme components as regulators of TAK1-induced PANoptosis. Loss of the catalytic subunit PPP6C significantly reduced TAK1-induced PANoptosis, while combined depletion of all three regulatory subunits (PPP6R1, PPP6R2, and PPP6R3) was required to block cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1, reducing the inhibitory S321 phosphorylation. These findings suggest that PP6 is a critical regulator of TAK1-induced PANoptosis and could be a potential therapeutic target for inflammatory conditions.The study investigates the role of protein phosphatase 6 (PP6) in TAK1-induced PANoptosis, a form of innate immune inflammatory lytic cell death. Through a CRISPR screen, the authors identified PP6 holoenzyme components as regulators of TAK1-induced PANoptosis. Loss of the catalytic subunit PPP6C significantly reduced TAK1-induced PANoptosis, while combined depletion of all three regulatory subunits (PPP6R1, PPP6R2, and PPP6R3) was required to block cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1, reducing the inhibitory S321 phosphorylation. These findings suggest that PP6 is a critical regulator of TAK1-induced PANoptosis and could be a potential therapeutic target for inflammatory conditions.