登上Nature Cancer封面：中科大刘连新团队等揭示相分离促进肝癌发展的新机制

Core Viewpoint - The study reveals that RIOK1 phase separation restricts PTEN translation via stress granules, promoting tumor growth in hepatocellular carcinoma (HCC) [4][12]. Group 1: Mechanism of Drug Resistance - RIOK1 phase separation mediates the formation of stress granules under TKI treatment stress, recruiting IGF2BP1 and G3BP1 to form dynamic stress granules [11]. - Stress granules selectively encapsulate PTEN mRNA, inhibiting its translation into PTEN protein, leading to the inactivation of the PTEN/PI3K/AKT pathway [11]. - The loss of PTEN activates the pentose phosphate pathway (PPP), increasing NADPH production and antioxidant capacity, helping cancer cells eliminate TKI-induced reactive oxygen species (ROS) [11]. Group 2: Key Findings and Clinical Relevance - The NRF2-RIOK1 regulatory axis is activated by oxidative stress (e.g., TKI treatment), upregulating RIOK1 expression and enhancing cancer cell adaptability through a positive feedback loop [11]. - The study establishes a causal chain linking stress granules, metabolic reprogramming, and TKI treatment resistance in HCC [12]. Group 3: Research Significance and Translational Directions - Targeting RIOK1 phase separation may disrupt the cancer cell's "stress buffering system," providing a new direction to improve TKI efficacy [12]. - Combination therapy of TKI and Chidamide may synergistically enhance anti-tumor effects [13]. - RIOK1 expression levels or the dynamics of stress granules could serve as predictive biomarkers for TKI efficacy, guiding personalized treatment [13].