Phospholipid phosphatase 2 drives liver repair and regeneration after acute liver injury

  • Signal Transduct Target Ther. 2026 Oct 8;11(1):436. doi: 10.1038/s41392-026-02825-y.
Fan Li  #  1  2  3 ,  Yiming Wang  #  4 ,  Pengyao Chen  #  1  2  3 ,  Jiongyuan Li  #  4 ,  Hao Wang  #  1  2  3 ,  Yunyun Xu  5 ,  Hui Wang  6 ,  Nan Zhang  4 ,  Tianning Huang  4 ,  Yi Wei  1 ,  Qingfa Bu  7 ,  Jiahao Si  1  2  3 ,  Jingwen Ma  1 ,  Xuehao Wang  1 ,  Qi Ling  8 ,  Haoming Zhou  1 ,  Xiaoxiao Liu  9 ,  Ling Lu  10  11  12  13 ,  Ming Ni  14  15  16
Affiliations
  • 1. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2. Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.
  • 3. Collaborative Innovation Center for Cancer Personalized Medicine and Hepatobiliary Center, Nanjing Medical University, Nanjing, China.
  • 4. Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China.
  • 5. Pediatric Clinical Research Institute, Children's Hospital of Soochow University, Suzhou, China.
  • 6. Department of Ultrasound, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 7. Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China.
  • 8. Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 9. Department of Radiation Oncology, Cancer Center, Affiliated Hospital of Xuzhou Medical University; Cancer Institute, Xuzhou Medical University, Xuzhou, China. [email protected].
  • 10. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 11. Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. [email protected].
  • 12. Collaborative Innovation Center for Cancer Personalized Medicine and Hepatobiliary Center, Nanjing Medical University, Nanjing, China. [email protected].
  • 13. Jiangsu Key Laboratory of Organ Transplantation and Transplant Immunology; Hepatobiliary Center, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. [email protected].
  • 14. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 15. Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. [email protected].
  • 16. Collaborative Innovation Center for Cancer Personalized Medicine and Hepatobiliary Center, Nanjing Medical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 42844243 DOI: 10.1038/s41392-026-02825-y
Abstract

Acute Liver Injury is commonly caused by overdose-drug, toxins, or ischemia. The liver possesses a remarkable regenerative capacity, wherein metabolic remodeling plays a crucial role in restoring hepatic function and homeostasis. However, the specific metabolic shift that initiates hepatocyte regeneration remains unclear. Here, we employed multi-time-point multi-omics analyses to demonstrate that phosphatidylethanolamine undergoes a dynamic metabolic reprogramming, with phospholipid Phosphatase 2 (PLPP2) exhibiting synchronous changes among the Enzymes regulating PE metabolism. Liver biopsy samples from patients with drug-induced Liver Injury corroborated the PLPP2 alterations. In murine models, hepatocyte-specific deletion of PLPP2 exacerbated acute Liver Injury. Mechanistically, the resolution of ER stress was accompanied by a robust upregulation of PLPP2 during the regenerative phase. This shift promotes liver repair and regeneration by initiating the PE biosynthesis. PE, upon binding to PEBP1, modulated its affinity and strengthened its interaction with GLI1, thereby disrupting the association between lTCH and GLI1 and preventing the ubiquitination and degradation of GLI1. Additionally, PE promotes Autophagy by facilitating the lipidation of LC3B. The increase in ER-localized PE mediated by PLPP2 also contributed to the alleviation of ER stress, thus establishing a positive feedback loop. Pharmacologic activation of PLPP2 or supplementation with ethanolamine may represent a promising therapeutic strategy for acute Liver Injury.

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