Pp1-87B/PPP1CC-JNK axis integrates apoptosis and ferroptosis-like cell death to regulate cell competition and tumorigenesis

Cell competition, an evolutionarily conserved quality control mechanism, selectively removes unfit or pre-malignant cells via cell-cell interactions. Through a genetic screen in Drosophila, we identify the phosphatase Pp1-87B as an essential regulator of JNK signaling crucial for eliminating scrib-deficient precancerous cells during tumor-suppressive cell competition. Mechanistically, impaired Pp1-87B activates JNK signaling via the Moe-Rho1 axis. Subsequently, JNK signaling acts as a central hub, integrating apoptosis and ferroptosis-like cell death by activating the Hippo signaling pathway. Critically, we demonstrate that the human ortholog, PPP1CC (protein phosphatase 1 catalytic subunit gamma), functions similarly to drive apoptosis and ferroptosis in human liver tumor cells through JNK activation. Collectively, our findings provide insights into the molecular integration of distinct cell death pathways during premalignant cell elimination in cell competition and identify PPP1CC as a promising therapeutic target for liver cancer treatment.