p38β-mediated BiP phosphorylation drives stemness and chemoresistance by suppressing UPR activation in hepatocellular carcinoma

Abstract Tumor-initiating cells (TICs) promote tumor initiation and therapy resistance, yet the kinase regulators that sustain TICs remain incompletely defined. Here, we identify the stress kinase p38β (MAPK11) supports TIC maintenance and drug resistance in hepatocellular carcinoma (HCC). Integrated analysis of chemotherapy-enriched HCC spheroids, and DepMap data prioritized p38β as a kinase linked to stemness and chemoresistance. High p38β expression correlates with poor prognosis and aggressive clinicopathological features in HCC patients. Mechanistically, p38β phosphorylates the endoplasmic reticulum (ER) chaperone BiP at threonine 648, enhancing its association with the unfolded protein response (UPR) sensors PERK and IRE1-α. This modification suppresses UPR activation and reduces unfolded protein accumulation, thereby preserving ER proteostasis under chemotherapeutic stress. Functionally, p38β-driven BiP phosphorylation sustains TIC phenotypes and cisplatin resistance in vitro and in vivo. BiP inhibition with HA15 restores UPR signaling and sensitizes patient-derived xenograft and organoid models to cisplatin, revealing a targetable p38β–BiP axis in HCC.