2. Academic Validation
  3. LTA4H improves the tumor microenvironment and prevents HCC progression via targeting the HNRNPA1/LTBP1/TGF-β axis

LTA4H improves the tumor microenvironment and prevents HCC progression via targeting the HNRNPA1/LTBP1/TGF-β axis

  • Cell Rep Med. 2025 Mar 18;6(3):102000. doi: 10.1016/j.xcrm.2025.102000.
Shuai Yang 1,  Xinyao Qiu 1,  Yingcheng Yang 2,  Jing Wu 3,  Shan Wang 4,  Bo Zheng 5,  Jianmin Wu 6,  Tao Zhou 4,  Yangqianwen Zhang 4,  Mixue Bai 4,  Shuowu Liu 4,  Zihan Zhao 4,  Yani Zhang 6,  Yixian Wang 6,  Jinxia Bao 7,  Mengye Wu 4,  Dongdong Xue 4,  Meiyu Bao 4,  Ji Hu 4,  Siyun Shen 4,  Hongyang Wang 8,  Lei Chen 9
Affiliations

Affiliations

  • 1 Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; National Center for Liver Cancer, Shanghai 200441, China.
  • 2 Hepatic Surgery Department, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China.
  • 3 National Center for Liver Cancer, Shanghai 200441, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 4 The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; National Center for Liver Cancer, Shanghai 200441, China.
  • 5 Department of hematology, Naval medical center, Naval Medical University, Shanghai 200052, China.
  • 6 Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
  • 7 Model Animal Research Center, Medical School, Nanjing University, Nanjing 210093, China.
  • 8 Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; National Center for Liver Cancer, Shanghai 200441, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai 200438, China. Electronic address: hywangk@vip.sina.com.
  • 9 Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; National Center for Liver Cancer, Shanghai 200441, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, China. Electronic address: chenlei@smmu.edu.cn.
PMID: 40056904 DOI: 10.1016/j.xcrm.2025.102000
Abstract

Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206+ macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.

Keywords

BLT1; CD206(+) macrophage; H3K27ac; HDAC1; HNRNPA1; LTA4H; LTBP1; TGF-β; hepatocellular carcinoma; immunotherapy resistance.

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