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

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 c...

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Published inCell reports. Medicine Vol. 6; no. 3; p. 102000
Main Authors Yang, Shuai, Qiu, Xinyao, Yang, Yingcheng, Wu, Jing, Wang, Shan, Zheng, Bo, Wu, Jianmin, Zhou, Tao, Zhang, Yangqianwen, Bai, Mixue, Liu, Shuowu, Zhao, Zihan, Zhang, Yani, Wang, Yixian, Bao, Jinxia, Wu, Mengye, Xue, Dongdong, Bao, Meiyu, Hu, Ji, Shen, Siyun, Wang, Hongyang, Chen, Lei
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 18.03.2025
Elsevier
Subjects
Advanced Basic Science
Animals
BLT1
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
CD206+ macrophage
Cell Line, Tumor
Disease Progression
Epoxide Hydrolases - genetics
Epoxide Hydrolases - metabolism
Female
Gene Expression Regulation, Neoplastic
H3K27ac
HDAC1
hepatocellular carcinoma
Heterogeneous Nuclear Ribonucleoprotein A1 - genetics
Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism
HNRNPA1
Humans
immunotherapy resistance
Latent TGF-beta Binding Proteins - genetics
Latent TGF-beta Binding Proteins - metabolism
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
LTA4H
LTBP1
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Signal Transduction
TGF-β
Transforming Growth Factor beta - metabolism
Tumor Microenvironment
HDAC1
H3K27ac
BLT1
TGF-β
immunotherapy resistance
LTA4H
HNRNPA1
LTBP1
hepatocellular carcinoma
CD206+ macrophage
CD206 + macrophage
CD206(+) macrophage
Online AccessGet full text
ISSN2666-3791
2666-3791
DOI10.1016/j.xcrm.2025.102000

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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. [Display omitted] •Downregulated LTA4H promotes HCC occurrence and progression•LTA4H ablation fosters CD206+ macrophage via LTBP1-mediated TGF-β activation•LTA4H prevents LTBP1 mRNA maturation and processing in an HNRNPA1-dependent manner•TGF-β blockage sensitizes LTA4H-deficient HCC to immunotherapy Yang et al. report that LTA4H deficiency promotes CD206+ macrophage polarization through upregulating LTBP1 and downstream TGF-β secretion and activation in HCC. Mechanistically, LTA4H induces HNRNPA1 phosphorylation, enhancing their interaction and leading to functional inhibition of HNRNPA1 in regulating LTBP1 mRNA processing.
AbstractList 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. •Downregulated LTA4H promotes HCC occurrence and progression•LTA4H ablation fosters CD206+ macrophage via LTBP1-mediated TGF-β activation•LTA4H prevents LTBP1 mRNA maturation and processing in an HNRNPA1-dependent manner•TGF-β blockage sensitizes LTA4H-deficient HCC to immunotherapy Yang et al. report that LTA4H deficiency promotes CD206+ macrophage polarization through upregulating LTBP1 and downstream TGF-β secretion and activation in HCC. Mechanistically, LTA4H induces HNRNPA1 phosphorylation, enhancing their interaction and leading to functional inhibition of HNRNPA1 in regulating LTBP1 mRNA processing.
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.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.
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. [Display omitted] •Downregulated LTA4H promotes HCC occurrence and progression•LTA4H ablation fosters CD206+ macrophage via LTBP1-mediated TGF-β activation•LTA4H prevents LTBP1 mRNA maturation and processing in an HNRNPA1-dependent manner•TGF-β blockage sensitizes LTA4H-deficient HCC to immunotherapy Yang et al. report that LTA4H deficiency promotes CD206+ macrophage polarization through upregulating LTBP1 and downstream TGF-β secretion and activation in HCC. Mechanistically, LTA4H induces HNRNPA1 phosphorylation, enhancing their interaction and leading to functional inhibition of HNRNPA1 in regulating LTBP1 mRNA processing.
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.
SummaryLeukotriene 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.
ArticleNumber 102000
Author Liu, Shuowu
Zheng, Bo
Wu, Jianmin
Hu, Ji
Zhou, Tao
Zhang, Yangqianwen
Shen, Siyun
Chen, Lei
Wu, Jing
Wu, Mengye
Bao, Meiyu
Xue, Dongdong
Zhang, Yani
Yang, Yingcheng
Wang, Hongyang
Yang, Shuai
Zhao, Zihan
Bao, Jinxia
Qiu, Xinyao
Bai, Mixue
Wang, Yixian
Wang, Shan
Author_xml – sequence: 1
  givenname: Shuai
  surname: Yang
  fullname: Yang, Shuai
  organization: Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
– sequence: 2
  givenname: Xinyao
  surname: Qiu
  fullname: Qiu, Xinyao
  organization: Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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  surname: Yang
  fullname: Yang, Yingcheng
  organization: Hepatic Surgery Department, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China
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  surname: Wu
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  organization: National Center for Liver Cancer, Shanghai 200441, China
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  surname: Wang
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  organization: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China
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  surname: Zheng
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  organization: Department of hematology, Naval medical center, Naval Medical University, Shanghai 200052, China
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  surname: Wu
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  organization: Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China
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  givenname: Yangqianwen
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  surname: Zhang
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  organization: Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China
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  surname: Xue
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  givenname: Hongyang
  surname: Wang
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  email: chenlei@smmu.edu.cn
  organization: Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Issue 3
Keywords HDAC1
H3K27ac
BLT1
TGF-β
immunotherapy resistance
LTA4H
HNRNPA1
LTBP1
hepatocellular carcinoma
CD206+ macrophage
CD206 + macrophage
CD206(+) macrophage
Language English
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Snippet Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various...
SummaryLeukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various...
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SourceType Open Access Repository
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StartPage 102000
SubjectTerms Advanced Basic Science
Animals
BLT1
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
CD206+ macrophage
Cell Line, Tumor
Disease Progression
Epoxide Hydrolases - genetics
Epoxide Hydrolases - metabolism
Female
Gene Expression Regulation, Neoplastic
H3K27ac
HDAC1
hepatocellular carcinoma
Heterogeneous Nuclear Ribonucleoprotein A1 - genetics
Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism
HNRNPA1
Humans
immunotherapy resistance
Latent TGF-beta Binding Proteins - genetics
Latent TGF-beta Binding Proteins - metabolism
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
LTA4H
LTBP1
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Signal Transduction
TGF-β
Transforming Growth Factor beta - metabolism
Tumor Microenvironment
Title LTA4H improves the tumor microenvironment and prevents HCC progression via targeting the HNRNPA1/LTBP1/TGF-β axis
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https://dx.doi.org/10.1016/j.xcrm.2025.102000
https://www.ncbi.nlm.nih.gov/pubmed/40056904
https://www.proquest.com/docview/3175399148
https://pubmed.ncbi.nlm.nih.gov/PMC11970384
Volume 6
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