Core Viewpoint - The study reveals that RIOK1 phase separation restricts PTEN translation via stress granules, promoting tumor growth in hepatocellular carcinoma (HCC) [2][3][6]. Group 1: Research Findings - RIOK1 is highly expressed in HCC and is associated with poor prognosis, activated by NRF2 under various stress conditions [6]. - RIOK1 facilitates liquid-liquid phase separation (LLPS) by incorporating IGF2BP1 and G3BP1 into stress granules, which sequester PTEN mRNA, reducing its translation [6]. - This process activates the pentose phosphate pathway, helping cells cope with stress and protecting them from the effects of tyrosine kinase inhibitors (TKIs) [6]. Group 2: Implications for Treatment - The small molecule Chidamide, a selective histone deacetylase inhibitor, can downregulate RIOK1 and enhance the efficacy of TKIs [6]. - RIOK1-positive stress granules were found in tumors of HCC patients resistant to Donafenib, indicating a potential target for overcoming drug resistance [6][7]. Group 3: Broader Context - The findings connect the dynamic changes of stress granules and metabolic reprogramming to the progression of HCC, suggesting potential strategies to improve TKI efficacy [7]. - A related article in Nature Cancer discusses how cancer cells form stress granules to adapt to stress and survive, highlighting the role of RIOK1-mediated phase separation in drug resistance [8].

Core Viewpoint - The study reveals that TDP-43 protein undergoes intra-condensate demixing within stress granules, leading to pathological aggregation, which is a key mechanism in neurodegenerative diseases like ALS and FTD [2][14][16] Group 1: Mechanism of TDP-43 Aggregation - TDP-43 aggregation occurs through two critical steps: exceeding a concentration threshold and oxidative stress, resulting in intra-condensate demixing [2][9] - The aggregation process is characterized by a fivefold increase in TDP-43 concentration within stress granules, alongside oxidative modifications that expose vulnerable cysteine residues [10][14] - The study identifies that the C-terminal domain (CTD) structural changes and the interaction of hydrophobic regions drive TDP-43 separation and liquid-to-solid phase transition [5][10][14] Group 2: Implications for Neurodegenerative Diseases - TDP-43 mislocalization and aggregation are common features in approximately 97% of ALS cases and 45% of FTD cases, indicating a widespread pathological mechanism [4][14] - The findings suggest that stress granules may act as "crucibles" for TDP-43 aggregation, providing new insights into the pathogenesis of various neurodegenerative diseases [16] - The research highlights the potential therapeutic value of targeting the intra-condensate demixing process to prevent TDP-43 aggregation in motor neurons [12][16]