Hypoxia-induced endoplasmic reticulum stress mediates lenvatinib resistance in hepatocellular carcinoma through the IRE1α-XBP1s-HIF1α pathway

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.