编辑丨王多鱼 排版丨水成文 在这项最新研究中，研究团队发现，与天然 突触后致密区 （ postsynaptic density，PSD） 类似，重构的 PSD 凝聚体形成了一种软玻璃材料，且没有不可逆淀 粉样结构的形成迹象。这种玻璃样 PSD 凝聚体的形成依赖于支架蛋白间特异性、多价相互作用介导的 PSD 蛋白网络渗流。破坏 Shank3 的 SAM 结构域介导的 寡聚化 （一种在Phelan-McDermid综合征患者中观察到的 SHANK3 基因突变，患者 临床为智力障碍、语言发育迟缓、自闭症和肌张力低下 ） ，会通过削弱网 络渗流，使 PSD 凝聚体变软 （由软玻璃样向近液态转变） ，进而损害突触传递和可塑性，并导致小鼠出现自闭症样行为。 该研究的核心发现： Shank3 的寡聚化使 PSD 凝聚物具有软玻璃样材料特性 蛋白质网络特性决定 PSD 凝聚物的物质特性； Shank3 寡聚化缺失使突触后致密区变软并损害突触可塑性； 物质特性对于生物凝聚体的功能至关重要。 细胞含有通过 相分离 形成的多种类型的 无膜细胞器 和 生物凝聚体 。这些细胞生物凝聚体具有广泛的物质特性，从牛顿流体到弹性固体。关于生物 ...

Core Viewpoint - The study reveals that lactylation of YTHDC1 at K82 enhances its phase separation, stabilizing oncogenic mRNA and promoting the progression of renal cell carcinoma (RCC) in a hypoxic environment [2][6][9]. Group 1: Research Findings - The research systematically mapped the lactylation profile of proteins under hypoxic conditions in RCC, focusing on the functional mechanism of YTHDC1 K82 lactylation [2][6]. - Elevated levels of global lysine lactylation (Kla) were found in human RCC tissues and cells, which promotes malignant development of RCC [6][7]. - YTHDC1 K82 lactylation, mediated by p300 under hypoxic conditions, promotes the malignancy of RCC both in vitro and in vivo [6][7]. Group 2: Mechanism of Action - YTHDC1 K82 lactylation enhances the phase separation of YTHDC1, leading to the expansion of nuclear condensates that protect oncogenic transcripts BCL2 and E2F2 from degradation by the PAXT-EXO complex [6][7][9]. - The study highlights that the increased lysine lactylation regulates the stability of YTHDC1 target genes, thereby facilitating the progression of RCC [9]. Group 3: Study Highlights - Quantitative lactylation proteomics analysis revealed high levels of lactylation modification proteins under hypoxic conditions [7]. - The study identifies a novel regulatory pathway involving YTHDC1 lactylation that opens new therapeutic targets in the intersection of tumor metabolism and RNA regulation [2][6].

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].