撰文丨王聪 编辑丨王多鱼 排版丨水成文 最近，关于 牛磺酸 的研究接连登上三大顶刊 Science 、 Cell 和 Nature ，这些研究揭示了 牛磺酸的新功 能—— 抗衰老 【1】 、 提高癌症治疗效果 【2】 、 抗肥胖 【3】 ，当然，也不都是好消息，今年 5 月份发 表在 Nature 上的一项则显示， 肿瘤微环境中的牛磺酸会促进白血病 【4】 。 2025 年 6 月 5 日，牛磺酸研究再次登上顶刊 Science ，来自美国国立卫生研究院国家老龄化研究所的研 究团队 ，发表了题为： Is taurine an aging biomarker? （牛磺酸是衰老标志物吗？） ， 直接质疑了牛磺 酸作为衰老的生物标志物的观点 【5】 。 该研究显示：1）成年期循环牛磺酸浓度不会随年龄增长而下降；2）个体间循环牛磺酸浓度的差异通常大 于其一生中的纵向变化，这限制了其作为衰老生物标志物的实用性；3）循环牛磺酸浓度与健康状况的功能 指标之间的关联取决于具体情境 （年龄、物种或队列） ——。 研究团队进一步得出结论—— 牛磺酸浓度与衰老之间没有明显关联，循环牛磺酸浓度也就不太可能成为一 种良好的衰老生物标志 ...

Core Insights - The article highlights significant research advancements published in the journal Nature on June 4, 2025, with a notable contribution from Chinese scholars, indicating a growing influence in the global scientific community [2][3][6][8]. Group 1: Medical Innovations - A new thrombectomy technique called "Milli-spinner thrombectomy" was developed, demonstrating over twice the efficiency of existing methods in clearing blood clots, which could enhance treatment success rates for stroke, heart disease, and pulmonary embolism [2]. - Research identified CREM as a critical regulatory factor in NK cell function, suggesting its potential as a therapeutic target to enhance CAR-NK cell anti-tumor efficacy [3]. - A study revealed a novel mechanism of red blood cell hemolysis induced by ischemic endothelial necroptosis in COVID-19 patients, proposing a new therapeutic intervention to alleviate microvascular obstruction [7]. Group 2: Genetic and Archaeological Discoveries - The study utilizing ancient DNA confirmed the existence of a two-clanned matrilineal community in Neolithic China, providing insights into early human social structures [2]. - Research on human Pol III transcription initiation offered structural insights that could enhance understanding of non-coding RNA synthesis regulation [8]. - The discovery of the preference of the human chromatin remodeler SMARCAD1 for subnucleosomes highlights its role in maintaining pluripotency in mouse embryonic stem cells [8]. Group 3: Technological Developments - A new method using a non-natural micropeptide called "killswitch" was developed to probe condensate microenvironments, linking these environments to cellular functions [4]. - The introduction of a soft-clamped topological waveguide for phonons represents a significant advancement in the field of phononic devices [5].

Core Viewpoint - The latest research published in Nature reveals that maternal iron deficiency during pregnancy can lead to significant impacts on fetal sex development, specifically causing XY mouse embryos to develop ovaries instead of testes [2][14]. Group 1: Research Findings - The study conducted by a team from Osaka University demonstrates that iron, particularly ferrous ions (Fe²⁺), plays a crucial role in activating male sex determination genes [2][11]. - The Sry gene, located on the Y chromosome, is essential for male development and is activated during a specific time window in embryonic development [3][11]. - Iron metabolism is linked to the expression of the Sry gene, where iron deficiency leads to increased suppression of Sry expression due to epigenetic modifications [5][11]. Group 2: Mechanisms of Action - The research indicates that iron accumulates in key cells responsible for sex determination, with iron-related gene expression significantly higher in these cells compared to others [6][11]. - Experiments showed that blocking iron supply resulted in decreased Sry expression and a shift in XY embryos towards female characteristics [7][11]. - Maternal iron deficiency, induced through dietary means or iron chelation, resulted in a notable percentage of XY offspring exhibiting sex reversal [8][9][11]. Group 3: Implications for Human Health - The findings suggest that severe maternal iron deficiency could be an underrecognized environmental risk factor for certain cases of 46-XY disorders of sex development in humans [14]. - The study emphasizes the importance of adequate iron intake during pregnancy to prevent anemia and ensure proper fetal sex development [14]. - This research challenges traditional views on iron's role, highlighting its influence on gene expression and fetal development, thus calling for nutritional interventions during pregnancy [14].

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 article discusses the advancements in CAR-T cell therapy, particularly focusing on a new iPSC-derived CAR-T cell targeting HER2, which aims to overcome challenges in treating solid tumors [2][3]. Group 1: Research Development - Fate Therapeutics developed an iPSC-derived CAR-T cell that preferentially targets HER2-positive tumors, addressing multiple barriers to efficacy in solid tumors through gene editing and engineering modifications [2][3]. - The CAR-T cells are designed to distinguish between tumor cells and normal cells, detecting truncated and misfolded HER2, while also knocking out genes that cause immune rejection and T cell exhaustion [3][4]. Group 2: Mechanisms and Enhancements - The CAR-T cells have been engineered to express IL-7R fusion protein for enhanced persistence, TGF-β-IL-18R to resist immunosuppressive tumor microenvironments, and CXCR2 to promote specific migration to solid tumor tissues [4][5]. - The study highlights the CAR's ability to differentiate between tumor and normal cells, and the engineered cells exhibit improved persistence and migration capabilities, along with resistance to TGF-β mediated suppression [5]. Group 3: Results and Implications - The iPSC-derived HER2-targeting CAR-T cells demonstrated strong anti-tumor activity in both in vitro and in vivo environments, with limited cytolytic activity against HER2-positive normal cells [3][5]. - The combination of CAR and high-affinity, non-cleavable CD16a Fc receptor allows for comprehensive multi-antigen targeting, enhancing therapeutic potential [3][5].

Core Viewpoint - The research conducted by Washington University and Altius Biomedical Science Institute successfully designed synthetic enhancers that are more efficient and simpler than natural enhancers, achieving unprecedented cell-type specificity in human cells through iterative deep learning technology [2][6]. Group 1: Research Challenges - Traditional enhancer discovery faces three major challenges: the vast number of candidate enhancers in the human genome, the lack of precision in existing enhancers that often activate multiple cell types, and the complexity of regulatory rules involving various transcription factor combinations and spatial arrangements [6]. Group 2: Research Methodology - The research team developed an iterative deep learning design system, which underwent two cycles of "design-experiment-optimize," starting from 29,891 natural enhancer MPRA activity data to train the model, resulting in the design of 1,037 synthetic enhancers [6]. - The model was refined using real measurement data of synthetic enhancers, reducing the training data volume by 30 times compared to previous generations, and introducing L2 regularization to prevent over-reliance on a single transcription factor [6]. - The second generation achieved a breakthrough with the design of 688 new enhancers, significantly increasing median expression levels in specific cell types, such as a 46.2-fold increase in HepG2 cells and a 6.7-fold increase in K562 cells [6][7]. Group 3: Research Highlights - The specificity of the deep learning-designed enhancers surpassed that of natural controls, and the sequence grammar used for synthetic enhancers was more compact than that of natural enhancers [8]. - Iterative retraining of synthetic enhancers led to designs with superior specificity, and the activity of synthetic enhancers was correlated with single-cell transcription factor expression [8]. Group 4: Applications - The research opens three major application directions: targeted gene therapy for liver cancer, customized tissue-specific enhancers for rare genetic diseases, and the construction of cell-type-specific biosensors in synthetic biology [10]. - This study marks a fundamental shift in the design paradigm of gene regulatory elements, moving from traditional methods to an AI-driven approach that significantly increases success rates [10].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 染色质重塑因子在细胞核小体动态调节中发挥着关键作用，对染色质包装、转录、复制和 DNA 修复都至关重要。 2025 年 6 月 4 日，清华大学 生命学院 陈柱成 团队与 郗乔然 团队合作，在国际顶尖学术期刊 Nature 上发表了题为： Subnucleosome preference of human chromatin remodeler SMARCAD1 的研究论文。 该研究发现了人源染色质重塑蛋白 SMARCAD1 对 亚核小体 的偏好性 ，并验证了 SMARCAD1 的 这一功能对小鼠胚胎干细胞多能 性维持 的重要 作用 。 核小体 （ nucleosome ） 是真核生物染色质的基本单元，经典的核小体由 147 bp DNA 缠绕组蛋白八聚体形成，其中组蛋白八聚体由两拷贝 H2A-H2B 二聚体 和一拷贝(H3-H4) 2 四聚体组成。染色质结构高度动态可塑，核小体在复制、转录、 DNA 损伤修复等过程中经历拆分和重新组装，从而产生不同的中间态，例如 DNA 解缠绕 （DNA unwrapping） 、六聚核小体 （hexasome） 和四聚核小体 （te ...

Core Viewpoint - The study highlights the role of metabolic reprogramming in promoting immune suppression in hepatocellular carcinoma (HCC), which is crucial for developing targeted and effective anti-tumor strategies [2][3]. Group 1: Research Findings - The research integrates multi-omics data, including metabolomics, transcriptomics, and single-cell sequencing, to elucidate how tumor cells produce and actively export N1-acetylspermidine (N1-Ac-Spd), leading to immune suppression [3][4]. - N1-Ac-Spd accumulates in HCC tissues and increases in paired plasma compared to non-tumor liver tissues, promoting tumor progression and weakening the efficacy of immune checkpoint blockade (ICB) therapy in preclinical models [4][6]. - Inflammatory macrophages enhance the expression of SAT1 in HCC cells, which increases the export of N1-Ac-Spd through the polyamine transporter SLC3A2, creating an immunosuppressive tumor microenvironment [5][6]. Group 2: Mechanistic Insights - N1-Ac-Spd activates SRC signaling in a charge-dependent manner, leading to the polarization of CCL1+ macrophages and recruitment of regulatory T cells, which diminishes the effectiveness of ICB therapy [5][6]. - Blocking the synthesis of N1-Ac-Spd or targeting SLC3A2, SAT1, or CCL1 can significantly enhance the anti-tumor effects of ICB therapy [5][6]. Group 3: Implications for Treatment - The findings reveal mechanisms by which metabolic reprogramming fosters an immunosuppressive tumor microenvironment, providing theoretical foundations and potential intervention targets for enhancing HCC treatment [6][9].

Core Viewpoint - The article discusses the evolution and potential of CAR-T cell therapy, particularly focusing on the emerging in vivo CAR-T approach, which aims to simplify the treatment process and reduce costs while maintaining efficacy [2][3][6]. Group 1: Current State of CAR-T Therapy - CAR-T cell therapy has become a leading treatment for various blood cancers, with a projected market size of $11 billion in 2023, expected to grow to $190 billion by 2034 [2]. - The traditional CAR-T therapy process is complex and time-consuming, requiring several weeks for preparation and costing upwards of $500,000, limiting accessibility for many patients [3][4]. Group 2: In Vivo CAR-T Development - In vivo CAR-T therapy aims to generate CAR-T cells directly within the body, significantly simplifying the production process and potentially reducing costs by an order of magnitude [6][7]. - Companies like Capstan Therapeutics and Azalea Therapeutics are at the forefront of developing in vivo CAR-T therapies, with significant investments from major pharmaceutical companies [7]. Group 3: Advantages of In Vivo CAR-T - In vivo CAR-T therapy eliminates the need for pre-treatment chemotherapy, reducing associated side effects and expanding the patient population that can benefit from the treatment [12]. - The risk of severe side effects, such as cytokine release syndrome (CRS), may be lower with in vivo CAR-T compared to traditional ex vivo methods [12]. Group 4: Challenges and Innovations - The delivery of CAR genes to the correct cells in vivo presents challenges, with companies exploring various methods, including targeted lipid nanoparticles and modified viral vectors [10][11]. - Capstan Therapeutics and others are shifting towards using lipid nanoparticles to deliver RNA, which may offer a safer alternative to viral vectors [15]. Group 5: Clinical Trials and Future Outlook - Several in vivo CAR-T therapies are currently in clinical trials, with expectations for increased activity in the field by 2025 and 2026 [19]. - The article highlights the growing interest and competition in the CAR-T space, with many companies striving to make CAR-T therapy more accessible and effective [19].

Core Viewpoint - The article discusses significant advancements in mitochondrial DNA (mtDNA) editing technologies, particularly focusing on the development of efficient base editors that can potentially treat mitochondrial diseases and create animal models for research [2][4][12]. Group 1: Historical Context and Technological Development - The history of biotechnology is marked by key discoveries, including the first restriction enzyme in 1968, the invention of PCR in 1985, and the application of CRISPR technology in 2013, which have all enhanced the ability to manipulate DNA and treat genetic diseases [2]. - While CRISPR has achieved remarkable success in editing nuclear DNA (nDNA), progress in mtDNA editing has lagged behind, despite its critical role in cellular energy production and the severe diseases caused by mtDNA mutations [2]. Group 2: Recent Innovations in mtDNA Editing - In 2020, a team led by Liu Ruqian developed a base editor, DdCBE, that enables C-to-T editing of mtDNA, followed by a 2022 advancement by a South Korean team that achieved A-to-G editing using a modified version of DdCBE [3]. - However, the efficiency of existing A-to-G editing methods remains low, making it challenging to create mtDNA mutation animal models or to directly correct pathogenic mtDNA mutations in vivo [3]. Group 3: Breakthroughs in Base Editing - On June 3, 2025, research teams from East China Normal University and Lingang Laboratory published two papers in Nature Biotechnology, introducing a high-performance mitochondrial adenine base editor, eTd-mtABE, which significantly improves editing efficiency and reduces off-target effects [4][11]. - The eTd-mtABE demonstrated an editing efficiency of up to 87% in human cells and a 145-fold increase in editing efficiency in rat cells, enabling the creation of auditory neuropathy and Leigh syndrome rat models with high mutation frequencies [9][11]. Group 4: Implications for Disease Models and Treatments - The research teams successfully used eTd-mtABE to construct rat models for auditory neuropathy and Leigh syndrome, achieving a 74% efficiency in generating Leigh syndrome models that exhibited severe motor and cardiac dysfunction [11]. - An improved DdCBE variant was engineered to achieve an average of 53% restoration of wild-type mtDNA in Leigh syndrome models, leading to significant recovery of muscle and cardiac functions to wild-type levels [12]. Group 5: Future Prospects - The development of eTd-mtABE and the enhanced DdCBE variant represents a powerful tool for both basic and translational research in mitochondrial function and disease [12]. - The advancements in precise mtDNA editing highlight the potential for future applications in larger animal models and clinical settings, paving the way for innovative treatments for mitochondrial diseases [14].