2. Academic Validation
  3. Pp1-87B/PPP1CC-JNK axis integrates apoptosis and ferroptosis-like cell death to regulate cell competition and tumorigenesis

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

  • Cell Rep. 2025 Sep 23;44(9):116240. doi: 10.1016/j.celrep.2025.116240.
Du Kong 1,  Zhongbo Li 2,  Sihua Zhao 3,  Xueliang Yang 4,  Jiadong Zheng 3,  Yifan Guo 3,  Wenyan Xu 3,  Han Gao 5,  Hanqing Guo 5,  Qiang Zhang 6,  Jian Zhu 7,  Xianjue Ma 8,  Bin Jin 9
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China. Electronic address: kongdu@email.sdu.edu.cn.
  • 2 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China.
  • 3 School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China.
  • 4 Department of Cell Biology and Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
  • 5 School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China.
  • 6 Department of Cell Biology and Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China. Electronic address: qiangzhang32@zju.edu.cn.
  • 7 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China. Electronic address: zhujian1204@163.com.
  • 8 School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China. Electronic address: maxianjue@westlake.edu.cn.
  • 9 Department of Hepatobiliary Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Organ Transplant Department, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Shandong Province Engineering Research Center for Multidisciplinary Research on Hepatobiliary and Pancreatic Malignant Tumors, Jinan 250033, Shandong, China. Electronic address: jinbin@sdu.edu.cn.
PMID: 40906558 DOI: 10.1016/j.celrep.2025.116240
Abstract

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.

Keywords

CP: Cancer; Drosophila; Hippo pathway; JNK pathway; PPP1CC; Pp1-87B; TSCC; ferroptosis; liver cancer; scrib; tumor-suppressive cell competition.

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