ArticleOncogene2024
Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt signaling.
Article in Oncogene, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- XBP1 signaling from tumor metabolic stress to myeloid driven immunotherapy resistance (Review).International journal of molecular medicine · 2026Review
- Regulatory Mechanisms of XBP1 in Tumorigenesis and Cancer Progression: Challenges and Therapeutic Strategies.Pharmaceuticals (Basel, Switzerland) · 2026Review
- The Interplay Between CaCells · 2026Review
- Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.Frontiers in immunology · 2026Review
- Protein quality control and antigen presentation in the development of hepatitis B-related hepatocellular carcinoma.Frontiers in pharmacology · 2026Review
- TMEM166 negatively regulates unfolded protein response to affect hepatocellular carcinoma cell growth and sorafenib resistance.Cell death & disease · 2025Article
- Integrated analysis of single-cell and bulk transcriptomics reveals cellular subtypes and molecular features associated with osteosarcoma prognosis.BMC cancer · 2025Article
- Roles of X-box binding protein 1 in liver pathogenesis.Clinical and molecular hepatology · 2025Review
- ATF6 Promotes Colorectal Cancer Growth and Stemness by Regulating the Wnt Pathway.Cancer research communications · 2024Article
- Article
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Authors and funding
14 authors at 7 institutions in 1 country.
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Abstract
Liver-specific Ern1 knockout impairs tumor progression in mouse models of hepatocellular carcinoma (HCC). However, the mechanistic role of IRE1α in human HCC remains unclear. In this study, we show that XBP1s, the major downstream effector of IRE1α, is required for HCC cell survival both in vitro and in vivo. Mechanistically, XBP1s transactivates LEF1, a key co-factor of β-catenin, by binding to its promoter. Moreover, XBP1s physically interacts with LEF1, forming a transcriptional complex that enhances classical Wnt signaling. Consistently, the activities of XBP1s and LEF1 are strongly correlated in human HCC and with disease prognosis. Notably, selective inhibition of XBP1 splicing using an IRE1α inhibitor significantly repressed the viability of tumor explants as well as the growth of tumor xenografts derived from patients with distinct Wnt/LEF1 activities. Finally, machine learning algorithms developed a powerful prognostic signature based on the activities of XBP1s/LEF1. In summary, our study uncovers a key mechanistic role for the IRE1α-XBP1s pathway in human HCC. Targeting this axis could provide a promising therapeutic strategy for HCC with hyperactivated Wnt/LEF1 signaling.
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