2. Academic Validation
  3. Pharmacological targeting of the mitochondrial phosphatase PTPMT1 sensitizes hepatocellular carcinoma to ferroptosis

Pharmacological targeting of the mitochondrial phosphatase PTPMT1 sensitizes hepatocellular carcinoma to ferroptosis

  • Cell Death Dis. 2025 Apr 6;16(1):257. doi: 10.1038/s41419-025-07581-5.
Miaomiao Li 1 2 3,  Yi Wang 3,  Xinyan Li 2,  Jiayi Xu 2,  Liangwen Yan 2,  Shenkang Tang 2 4,  Chenyue Liu 5,  Mengjiao Shi 2 6,  Rongrong Liu 2,  Yaping Zhao 2,  Yi Zhang 2,  Lan Yang 2,  Yinggang Zhang 2,  Gang Wang 1 7,  Zongfang Li 6 8,  Ying Guo 9 10,  Yetong Feng 11 12,  Pengfei Liu 13 14 15
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, China.
  • 4 Department of Oncology, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China.
  • 5 Department of Medical Image, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 6 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 7 Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China.
  • 8 Department of General Surgery, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 9 International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. guoying.2yuan@xjtu.edu.cn.
  • 10 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. guoying.2yuan@xjtu.edu.cn.
  • 11 International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. fengyetong@xjtu.edu.cn.
  • 12 Core Research Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. fengyetong@xjtu.edu.cn.
  • 13 International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. liupengfei@xjtu.edu.cn.
  • 14 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. liupengfei@xjtu.edu.cn.
  • 15 Key Laboratory of Environment and Genes Related To Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China. liupengfei@xjtu.edu.cn.
PMID: 40189563 DOI: 10.1038/s41419-025-07581-5
Abstract

Protein tyrosine Phosphatase mitochondrial 1 (PTPMT1), is a member of the protein tyrosine Phosphatase superfamily localized on the mitochondrial inner membrane, and regulates the biosynthesis of cardiolipin. Given the important position of PTPMT1 in mitochondrial function and metabolism, pharmacological targeting of PTPMT1 is considered a promising manner in disease treatments. In this study, we mainly investigated the role of PTPMT1 in hepatocellular carcinoma (HCC) Ferroptosis, a new type of cell death accompanied by significant iron accumulation and lipid peroxidation. Herein, the pharmacological inhibition of PTPMT1 was induced by alexidine dihydrochloride (AD, a dibiguanide compound). Human HCC cell lines with PTPMT1 knockout and PTPMT1 overexpression were established using CRISPR/Cas9 and lentiviral transduction methods, respectively. The position of PTPMT1 in regulating HCC Ferroptosis was evaluated in vitro and in vivo. Our results indicated that pharmacological inhibition of PTPMT1, facilitated by AD treatment, heightens the susceptibility of HCC to cystine deprivation-ferroptosis, and AD treatment promoted the conversion from ferritin-bound Fe3+ to free Fe2+, which contributed to the labile iron pool in cytoplasm. Meanwhile, pharmacological inhibition of PTPMT1 also induced the formation of both swollen mitochondria and donut mitochondria, and enhanced the metabolism process form succinate to fumarate in mitochondrial tricarboxylic acid (TCA) cycle, which increased the sensitivity of HCC cells to cystine deprivation-induced Ferroptosis. In total, our work reveals the close association of PTPMT1 with cysteine deprivation-induced Ferroptosis, providing a novel insight into chemotherapy strategies against human HCC.

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