PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis
Background & Aims: Deletion of 15–21 nucleotides covering the preS1 start codon frequently occurs in patients with chronic HBV (CHB) with HBV genotype C and has been reported to be related to progression to hepatocellular carcinoma (HCC). However, the underlying mechanism causing the distinc...
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Elsevier
2025-03-01
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| Series: | JHEP Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555924002787 |
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| author | Yu-Min Choi Junghwa Jang Dong Hyun Kim Ziyun Kim Eunseo Kim Won Hyeok Choe Bum-Joon Kim |
| author_facet | Yu-Min Choi Junghwa Jang Dong Hyun Kim Ziyun Kim Eunseo Kim Won Hyeok Choe Bum-Joon Kim |
| author_sort | Yu-Min Choi |
| collection | DOAJ |
| description | Background & Aims: Deletion of 15–21 nucleotides covering the preS1 start codon frequently occurs in patients with chronic HBV (CHB) with HBV genotype C and has been reported to be related to progression to hepatocellular carcinoma (HCC). However, the underlying mechanism causing the distinct phenotype of this HBV variant remains largely unknown. We investigated the mechanism by which preS1Del is related to liver disease progression and enhanced HBV replication, focusing on endoplasmic reticulum (ER) stress. Methods: The effects of HBV replicative capacity, ER stress signaling, inflammation, cell death, and tumorigenesis resulting from PreS1 deletions were investigated through in vitro and in vivo experiments. Inhibitors of the IRE1-JNK pathway and IL6 blockade were used to examine HCC tumor load induced by preS1 deletions. Results: The PreS1Del variant selectively activates the IRE1 pathway, mainly via enhanced colocalization between the ER and HBsAg in infected hepatocytes. This leads to enhanced HBV replication and production of tumor-promoting inflammatory cytokines and IL6 and COX2 via the IRE1-JNK signaling pathway. Furthermore, in vivo data showed that the activation of IRE1-JNK signaling consequently leads to lipid accumulation and apoptosis within 21Del-HBV-infected hepatocytes, collectively driving severe tumorigenesis in the liver. Notably, several inhibitors of the IRE1-JNK pathway dramatically inhibited HBV replication and inflammation induced by 21Del-HBV but not by the wild-type HBV in infected hepatocytes. Furthermore, IL6 blockade significantly reduced HCC tumor load induced by 21Del-HBV. Conclusions: PreS1Del leads to enhanced HBV replication and HCC development through IRE1-JNK-IL6/COX2-mediated hepatocyte proliferation and liver inflammation. Inhibitors interfering with the IRE1-JNK-IL6 pathway could selectively inhibit HBV replication and inflammation in preS1Dels, suggesting their potential for the treatment of patients with CHB with preS1-deleted HBV variants. Impact and implications:: Deletion of 15–21 nucleotides at the preS1 start codon is common in patients with CHB with HBV genotype C and is linked to HCC progression. However, the mechanisms underlying the distinct phenotype of this variant remain largely unknown. We found that the preS1Del variant selectively activates the IRE1 pathway, primarily through enhanced IRE1-JNK-IL6 signaling. Inhibition of either the IRE1-JNK pathway or IL6 reduced HBV replication and tumor load in in vivo HCC models. This study enhances our understanding of the mechanisms of liver disease progression caused by 5ʹ preS1Del variants and provides new insights into treatment strategies for patients with these variants. We believe our findings will resonate with a diverse audience, including patients and their physicians, the medical community, academia, the life sciences sector, and the general public. |
| format | Article |
| id | doaj-art-5146a87427fa40419f51b439c1916cf4 |
| institution | Kabale University |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | JHEP Reports |
| spelling | doaj-art-5146a87427fa40419f51b439c1916cf42025-02-03T04:16:51ZengElsevierJHEP Reports2589-55592025-03-0173101274PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axisYu-Min Choi0Junghwa Jang1Dong Hyun Kim2Ziyun Kim3Eunseo Kim4Won Hyeok Choe5Bum-Joon Kim6Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea; Institute of Endemic Disease, Seoul National University Medical Research Center, Seoul, Republic of KoreaDepartment of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of KoreaDepartment of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of KoreaDepartment of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of KoreaDepartment of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of KoreaDepartment of Internal Medicine, Konkuk University School of Medicine, Seoul 05030, Republic of KoreaDepartment of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea; Institute of Endemic Disease, Seoul National University Medical Research Center, Seoul, Republic of Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; Seoul National University Medical Research Center (SNUMRC), Seoul 03080, Republic of Korea; BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea; Corresponding author. Address: Department of Microbiology and Immunology, College of Medicine, Seoul National University, 103, Daehak-ro, Jongno-gu, Seoul, Republic of Korea. Tel.:+82 2 740 8315; fax: +82 2 743 0881.Background & Aims: Deletion of 15–21 nucleotides covering the preS1 start codon frequently occurs in patients with chronic HBV (CHB) with HBV genotype C and has been reported to be related to progression to hepatocellular carcinoma (HCC). However, the underlying mechanism causing the distinct phenotype of this HBV variant remains largely unknown. We investigated the mechanism by which preS1Del is related to liver disease progression and enhanced HBV replication, focusing on endoplasmic reticulum (ER) stress. Methods: The effects of HBV replicative capacity, ER stress signaling, inflammation, cell death, and tumorigenesis resulting from PreS1 deletions were investigated through in vitro and in vivo experiments. Inhibitors of the IRE1-JNK pathway and IL6 blockade were used to examine HCC tumor load induced by preS1 deletions. Results: The PreS1Del variant selectively activates the IRE1 pathway, mainly via enhanced colocalization between the ER and HBsAg in infected hepatocytes. This leads to enhanced HBV replication and production of tumor-promoting inflammatory cytokines and IL6 and COX2 via the IRE1-JNK signaling pathway. Furthermore, in vivo data showed that the activation of IRE1-JNK signaling consequently leads to lipid accumulation and apoptosis within 21Del-HBV-infected hepatocytes, collectively driving severe tumorigenesis in the liver. Notably, several inhibitors of the IRE1-JNK pathway dramatically inhibited HBV replication and inflammation induced by 21Del-HBV but not by the wild-type HBV in infected hepatocytes. Furthermore, IL6 blockade significantly reduced HCC tumor load induced by 21Del-HBV. Conclusions: PreS1Del leads to enhanced HBV replication and HCC development through IRE1-JNK-IL6/COX2-mediated hepatocyte proliferation and liver inflammation. Inhibitors interfering with the IRE1-JNK-IL6 pathway could selectively inhibit HBV replication and inflammation in preS1Dels, suggesting their potential for the treatment of patients with CHB with preS1-deleted HBV variants. Impact and implications:: Deletion of 15–21 nucleotides at the preS1 start codon is common in patients with CHB with HBV genotype C and is linked to HCC progression. However, the mechanisms underlying the distinct phenotype of this variant remain largely unknown. We found that the preS1Del variant selectively activates the IRE1 pathway, primarily through enhanced IRE1-JNK-IL6 signaling. Inhibition of either the IRE1-JNK pathway or IL6 reduced HBV replication and tumor load in in vivo HCC models. This study enhances our understanding of the mechanisms of liver disease progression caused by 5ʹ preS1Del variants and provides new insights into treatment strategies for patients with these variants. We believe our findings will resonate with a diverse audience, including patients and their physicians, the medical community, academia, the life sciences sector, and the general public.http://www.sciencedirect.com/science/article/pii/S25895559240027875ʹ preS1 deletionsER stressIRE1-JNK signalingLipogenesisApoptosisInflammation |
| spellingShingle | Yu-Min Choi Junghwa Jang Dong Hyun Kim Ziyun Kim Eunseo Kim Won Hyeok Choe Bum-Joon Kim PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis JHEP Reports 5ʹ preS1 deletions ER stress IRE1-JNK signaling Lipogenesis Apoptosis Inflammation |
| title | PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis |
| title_full | PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis |
| title_fullStr | PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis |
| title_full_unstemmed | PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis |
| title_short | PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis |
| title_sort | pres1 deletions in genotype c hbv leads to severe hepatic inflammation and hepatocarcinogenesis via the ire1 jnk axis |
| topic | 5ʹ preS1 deletions ER stress IRE1-JNK signaling Lipogenesis Apoptosis Inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2589555924002787 |
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