RIOK1 Phase Separation Shapes Stress Adaptation and Cell Fate in Hepatocellular Carcinoma

Cancer cells can always be unexpected rescued from desperate environment by mounting adaptive responses to resolve the arising cellular stress. The dynamic stress granules (SGs) assembly and metabolic reprogramming play crucial roles in maintaining cellular growth and homeostasis. However, the mechanisms underlying their interaction remain elusive. Here we screened RIOK1 is highly expressed in liver cancer tissues and is transactivated by NRF2 under stressful conditions. Mechanistically, the oncogenic phenotype observed in hepatocellular carcinoma (HCC) cells is associated with the capacity of RIOK1 to undergo liquid-liquid phase separation. The non-enzymatic regulation of IGF2BP1 tyrosine phosphorylation by RIOK1 contributes to incorporating RIOK1/IGF2BP1/G3BP1 into stress granules which concurrently sequester PTEN mRNA. The decrease in PTEN translation concomitantly activates the pentose phosphate pathway to resolve stress and confer cytoprotection. Additionally, chidamide downregulates RIOK1 expression and enhances the efficacy of TKIs, presenting a promising therapeutic strategy for HCC treatment.