撰文丨王聪 编辑丨王多鱼 排版丨水成文 最近几年，以 司美格鲁肽 为代表的 GLP-1 类药物几乎无处不在，它们帮助了许多人安全的控制糖尿病和减肥，此外，这类药物还能降低心血管疾病风险、治疗 睡眠呼吸暂停、骨关节炎，甚至还有助于戒烟戒酒、缓解阿尔茨海默病等疾病。 GLP-1 类药物的畅销，并非一朝一夕。从发现 GLP-1 激素，解析其作用机制，再开发为糖尿病和肥胖的治疗药物，这一旅程漫长而曲折，跨越了 40 多年时 间，涉及学术界和制药行业的数百名研究人员，而诺贝尔奖至多授予 3 人，如果今年的诺贝尔生理学或医学奖奖授予 GLP-1 的发现和相关药物开发，谁值得获 奖？ 对 GLP-1 的结构和功能的早期认识是基于 Joel Habener、 Jens Juul Holst、 Svetlana Mojsov 、 Dan Drucker 几人的研究，而诺和诺德的研究人员 Lotte Bjerre Knudsen 开发了基于 GLP-1 的药物利拉鲁肽和司美格鲁肽。 如果 GLP-1 研究获得诺贝尔奖的认可，那么获奖者大概率是从这 5 人中产生。而在去年，"诺奖风向标"之一的拉斯克奖授予了其中 3 人 —— Jo ...

Core Viewpoint - The article discusses the advancements in CAR-T cell therapy, particularly focusing on enhancing its efficacy against low-antigen expressing cancers through the integration of intrinsically disordered regions (IDR) with CAR molecules [2][4][6]. Group 1: CAR-T Cell Therapy Overview - CAR-T cells have shown unprecedented success in treating hematological malignancies and are being explored for various diseases, including cancers, infections, autoimmune diseases, and fibrosis [2]. - A significant limitation of CAR-T therapy is its low sensitivity to antigens, requiring hundreds of antigen molecules for activation, which restricts its application to cancers with high antigen expression [2][3]. Group 2: Research Findings - A study published by a team from Yale University demonstrated that fusing IDR with CAR molecules enhances the cytotoxicity of CAR-T cells against low-antigen cancers by promoting biomolecular condensation [4][6]. - The research involved constructing CAR-IDR fusion proteins targeting CD19, CD22, and HER2, which improved the binding of CAR-T cells to cancer cell targets and increased the release of cytotoxic factors [6][8]. Group 3: Implications of IDR Integration - The integration of IDR into CAR-T cells resulted in better anti-tumor effects in both hematological and solid tumor models without spontaneous activation in the absence of antigens, indicating a novel mechanism of action [8]. - This approach expands the toolkit for CAR engineering, suggesting that IDR can serve as a new modular element to enhance the anti-tumor efficacy of CAR-T cells [8].

Core Viewpoint - The article highlights the significance of transfection technology in life sciences and medical research, emphasizing the breakthrough of ProteanFect, a novel transfection product based on protein coacervates, which addresses the longstanding "transfection challenge" faced by researchers [1][2]. Group 1: Transfection Technology and Challenges - Transfection technology is crucial for exploring complex mechanisms of diseases and developing innovative therapies, yet researchers have struggled with traditional methods that have limitations such as low stability and safety concerns [1]. - Traditional methods like liposomes, viral vectors, and electroporation often lead to cell damage, particularly when working with precious samples like primary immune cells and neurons [1]. Group 2: Introduction of ProteanFect - ProteanFect is the world's first transfection product based on protein coacervates, designed to overcome the limitations of traditional methods by achieving high delivery efficiency with low cytotoxicity [1][2]. - Since its launch, ProteanFect has gained recognition as a comprehensive solution in the industry, validated by solid experimental data and positive user feedback [2]. Group 3: Mechanism and Functionality - The product utilizes the natural phenomenon of liquid-liquid phase separation (LLPS) to form coacervates that mimic cellular transport and regulatory mechanisms, allowing for efficient delivery of nucleic acids into cells [4][8]. - Upon entering the cell, the coacervates disassemble, releasing nucleic acids that perform their biological functions while the carrier proteins are naturally degraded [11]. Group 4: Versatility and Applications - ProteanFect is capable of efficiently transfecting various cell lines and challenging primary cells without the need for viral packaging or electroporation, making it suitable for a wide range of applications [14][16]. - The product supports multiple experimental scenarios, including overexpression, knockdown, knockout, and co-transfection, with a simplified component structure that enhances its usability [21][22]. Group 5: Performance and Efficiency - ProteanFect demonstrates high loading capacity and expression levels, allowing for the delivery of larger nucleic acid fragments and multiple biomolecules simultaneously, thus expanding the possibilities for gene therapy and complex gene regulation studies [24][26]. - The preparation process for ProteanFect is straightforward, requiring only a one-minute mixing of protein and nucleic acids before cell incubation, which significantly saves time and costs in experimental workflows [29]. Group 6: Customer Support and Value Proposition - The company provides not just high-quality research products but a complete solution that includes pre-sale customization and post-sale technical support, aiming to eliminate technical barriers for researchers [33].

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].

Core Viewpoint - The study reveals that the oligomerization of Shank3 regulates the material properties of postsynaptic density (PSD) condensates, which are crucial for synaptic plasticity and neuronal functions related to learning and memory [3][5][7]. Summary by Sections - The research team from Southern University of Science and Technology published findings indicating that PSD condensates exhibit soft-glass-like properties, with Shank3 protein oligomerization playing a key role in governing these material characteristics [3][5]. - The study found that the reconstructed PSD condensates formed a soft-glass material without signs of irreversible amyloid-like structures. This glass-like formation relies on specific, multivalent interactions among scaffold proteins, which mediate the network flow of PSD proteins [4]. - Disruption of Shank3's SAM domain-mediated oligomerization, observed in patients with Phelan-McDermid syndrome, leads to a softening of PSD condensates, impairing synaptic transmission and plasticity, and resulting in autism-like behaviors in mice [4][5]. - Overall, the research emphasizes the importance of the material properties of PSD condensates in neuronal synaptic functions related to learning and memory [7].

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].