Hypoxia-induced endoplasmic reticulum stress mediates lenvatinib resistance in hepatocellular carcinoma through the IRE1α-XBP1s-HIF1α pathway
- J Cancer Res Clin Oncol. 2026 May 21;152(7):138. doi: 10.1007/s00432-026-06504-x.
- 1. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
- 2. Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
- 3. Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
- 4. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China. [email protected].
- 5. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China. [email protected].
- # Contributed equally.
Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally, with a dismal prognosis for advanced patients. Lenvatinib, a first-line anti-angiogenic agent, has improved clinical outcomes, but drug resistance remains a major unmet clinical need. Hypoxia, a hallmark of solid tumors, crosstalks with endoplasmic reticulum stress (ERS), yet their combined role in lenvatinib resistance in HCC remains undefined.
Methods: TCGA and GEO datasets were analyzed for ERS-related gene expression and prognostic value. In vitro experiments were conducted in HepG2 and HCCLM3 cells under normoxic (21% O₂) or hypoxic (1% O₂) conditions. Cell viability, Apoptosis, migration, and protein expression were assessed via standard assays. siRNA silencing and the ERS inhibitor 4-PBA were used for mechanistic validation.
Results: The ERS marker GRP78 was significantly upregulated in HCC tissues and correlated with poor survival. Hypoxia induced ERS in HCC cells, promoting proliferation and migration while attenuating lenvatinib-induced Apoptosis. Mechanistically, hypoxia induces activation of the IRE1α-XBP1s-HIF1α axis, and genetic silencing of this axis restores lenvatinib sensitivity. 4-PBA effectively reversed hypoxia-mediated drug resistance.
Conclusions: Hypoxia-induced ERS mediates lenvatinib resistance in HCC via the IRE1α-XBP1s-HIF1α pathway. Targeting this axis provides a promising strategy to overcome anti-angiogenic therapy resistance in HCC.