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

• Published in: Cell 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
• Language: English
• 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
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2025.102000

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.