Endoplasmic reticulum stress upregulate HYOU1 and mediates lenvatinib resistance in liver cancer through ERK/MAPK pathway

Endoplasmic reticulum stress (ERS) is commonly observed in liver cancer and is associated with drug sensitivity. Consequently, ERS-related genes may serve as targets for enhancing treatment sensitivity. This study analyzed RNA and proteomic sequencing data from induced and non-induced ERS and identified hypoxia-upregulated protein 1 (HYOU1) as an ERS-related gene. We confirmed that ERS regulated HYOU1 expression. Database and microarray analyses revealed that HYOU1 expression level was significantly higher in cancer tissues than in normal tissues (P < 0.05). Additionally, HYOU1 upregulation correlated with poor clinical outcomes (P < 0.05). Findings from animal experiments, CCK-8 assays, colony formation assays, wound healing assays, transwell assays, and flow cytometry results showed that HYOU1 decreased the inhibition of cell proliferation, migration, invasion, and tumor growth while inducing apoptosis. Conversely, HYOU1 overexpression caused the opposite effects. Combining RNA-sequencing data from HYOU1 knockdown and Western blot (WB) results, we have, for the first time, identified that HYOU1 activates the ERK/MAPK pathway. We show that ERS promotes resistance to lenvatinib, whereas HYOU1 knockdown increases sensitivity to lenvatinib. We believe that HYOU1 plays a crucial role in treating lenvatinib-resistant liver cancer.