Core Viewpoint - The study highlights the pathogenic role of meningeal B cells in driving neuroinflammation relapses in central nervous system autoimmune diseases, particularly multiple sclerosis (MS) [2][6]. Group 1: Research Findings - Meningeal autoreactive B cells interact with antigen-specific T cells, accelerating neuroinflammation [3][6]. - In an experimental autoimmune encephalomyelitis (EAE) mouse model, meningeal autoreactive B cells amplify local pro-inflammatory mechanisms through their interaction with T cells, promoting neutrophil recruitment and endothelial cell activation prior to clinical disease onset [4][6]. - The mechanism requires B cells to express major histocompatibility complex class II (MHC II) molecules and T cells to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) [5]. Group 2: Implications for Treatment - The findings confirm that local autoreactive B cells in the brain are key initiators of neuroinflammation in relapsing MS and represent promising therapeutic targets [6][7]. - Selective depletion of brain-resident B cells can alleviate relapses in experimental autoimmune encephalomyelitis [7].

Core Insights - The article discusses a groundbreaking study published in "Nature Medicine" that reveals the significant role of gut microbiota in the development and management of type 2 diabetes (T2DM) through metabolic reprogramming [3][4][8]. Group 1: Research Findings - The study integrates multi-omics analysis to elucidate the molecular mechanisms by which gut microbiota influences glucose metabolism, highlighting the interaction between gut microbiota and blood metabolites [3][6][11]. - It identifies 502 metabolites significantly associated with glucose metabolism abnormalities, with a notable contribution of gut microbiota accounting for nearly 30% of blood metabolite variation [8][9]. - Specific microbial species were linked to key metabolites, indicating their potential as intervention targets for diabetes management [9][11]. Group 2: Clinical Implications - The research suggests a paradigm shift in diabetes treatment from mere pharmacological control to metabolic restoration through personalized dietary interventions and gut microbiota modulation [4][10]. - Clinical trials showed that 65% of participants achieved normalized glucose metabolism indicators after 12 months of personalized dietary intervention, closely related to gut microbiota reprogramming [3][4]. - The findings emphasize the importance of early intervention and personalized strategies in diabetes prevention and management, potentially reducing the risk of complications [4][12]. Group 3: Methodology and Validation - The study utilized a dual-cohort design with high-throughput metabolomics to analyze 978 plasma metabolites and identified 1,427 microbial gene clusters [6][7]. - Machine learning algorithms were employed to establish predictive models for metabolite levels based on clinical indicators, dietary intake, and microbiota characteristics, enhancing the reliability of the findings [7][8]. - An interactive network platform was developed to facilitate global research collaboration and data analysis, promoting the advancement of personalized diabetes intervention strategies [7][10].

Core Findings - Researchers from the University of Konstanz and Queen Mary University of London have identified a key molecular signal, chemokine CXCL12, which induces erythroid progenitor cells to expel their nuclei, a critical step in red blood cell maturation [1][2] - This discovery provides a new pathway for large-scale production of artificial blood, addressing the long-standing challenges in artificial hematopoiesis research [1] Group 1: Research Significance - The process of blood generation in the human body is complex and not fully understood, with blood naturally produced in the bone marrow [1] - CXCL12, primarily found in the bone marrow, plays a crucial role in inducing erythroid progenitor cells to expel their nuclei, allowing for more efficient oxygen transport [1] Group 2: Implications for Artificial Blood Production - The ability to trigger the nuclear expulsion process in erythroid progenitor cells using CXCL12 could significantly enhance the efficiency of artificial blood production [2] - Future large-scale and personalized production of artificial blood could alleviate blood shortages, enable targeted synthesis of rare blood types, and facilitate autologous blood regeneration for precise treatments of diseases such as cancer and genetic disorders [2]

Core Viewpoint - Ferroptosis is a newly regulated form of programmed cell death closely related to various liver diseases, with a lack of specific covalent inhibitors targeting ferroptosis [2][3]. Group 1: Research Findings - The research team identified Rociletinib (ROC), an EGFR inhibitor in clinical trials, as a potent ferroptosis inhibitor through virtual screening and mechanistic studies [4]. - ROC covalently binds to the 170th cysteine of the ACSL4 protein, inhibiting its enzymatic activity, thereby suppressing lipid peroxidation and subsequent ferroptosis [5][8]. - ROC effectively alleviates acute liver injury mediated by ferroptosis in mouse models, establishing it as a promising therapeutic strategy for ferroptosis-related diseases [7][8]. Group 2: Target and Mechanism - ACSL4 is a key enzyme in lipid metabolism and its abnormal activation leads to ferroptosis, making it an important therapeutic target for ferroptosis-related diseases [3]. - The study highlights ROC as a direct covalent inhibitor targeting ACSL4, providing a new avenue for treatment [7].

Core Insights - The research team from the University of Texas at Arlington has identified the IDO1 enzyme as a key player in cholesterol metabolism, suggesting that inhibiting this enzyme could help maintain healthy cholesterol levels and offer new hope for treating major diseases such as heart disease, diabetes, and cancer [1][2] Group 1: Enzyme Role and Mechanism - The study reveals that blocking the IDO1 enzyme significantly suppresses the inflammatory response of macrophages, which is crucial since chronic inflammation is a common trigger for diseases like heart disease, cancer, diabetes, and Alzheimer's [1] - IDO1 enzyme activation leads to the production of kynurenine, which interferes with macrophages' ability to process cholesterol, indicating a direct link between inflammation and cholesterol metabolism [1] Group 2: Implications for Disease Treatment - The research indicates that targeting both IDO1 and nitric oxide synthase may provide revolutionary therapies for millions of patients suffering from inflammation-driven diseases [1] - The team is exploring the network relationship between IDO1 and cholesterol regulation, aiming to identify other enzymes that may be involved, which could lead to the development of safe and effective IDO1 inhibitors [2]

Core Insights - The research led by Sun Yat-sen University First Affiliated Hospital and Rutgers University has identified a transmembrane protein called NINJ1, which plays a significant role in the mechanical rupture of cell membranes, potentially offering new therapeutic avenues for treating sepsis and inflammation-related diseases [1][2] Group 1: Research Findings - The study reveals that NINJ1 significantly influences the probability of membrane rupture under mechanical stress across various cell types, indicating its role in maintaining membrane stability even in the absence of inflammatory pathways [1] - When NINJ1 is active, cell membranes are more prone to rupture under pressure; conversely, its knockout results in membranes that are unusually robust and pressure-resistant [2] Group 2: Clinical Implications - NINJ1 may serve as a novel target for regulating stress-related tissue damage, excessive inflammatory responses, and autoimmune diseases, particularly in conditions like lung injury, sepsis, or tumor microenvironments [2] - The potential therapeutic approach involves using small molecule drugs or nanoantibodies to inhibit NINJ1 activity, which could help control the release of damage-associated molecular patterns and reduce tissue destruction in sepsis-related inflammatory storms [2]

2025 年 6 月 12 日，浙江大学 林爱福 、 周天华 、 袁瑛 等人在 Cell 子刊 Molecular Cell 上发表了题为 ： Hepatic micropeptide modulates mitochondrial RNA processing machinery in hepatocellular carcinoma 的研究论文。 该研究发现并描述了以一类与 肝细胞癌 （HCC） 相关的 微肽 ，并揭示了它们调控 肝细胞癌中的线粒体 RNA 加工的机制， 为癌症的诊断和治疗提供了新思 路。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 微肽 （ micropeptide ） 源自非经典翻译，是具有维持组织稳态和促进癌症发展等关键作用的新型生物分子。然而， 肝细胞癌 （HCC） 中微肽的蛋白质组学图 谱和功能机制在很大程度上仍不清楚。 从机制上来说，能量应激诱导的 MRPIP 通过与 HSD17B10 的 R25 残基相互作用，阻碍了线粒体核糖核酸酶 P （mtRNase P） 复合物的组装，这破坏了 HSD17B10 的四聚化以及随后的 HSD17B10-TRMT10C 子复合物的形成，从而导致 ...

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 development of a large-scale Pan-Cancer Proteome Atlas (TPCPA) that aims to enhance the understanding of cancer biology and identify therapeutic targets and biomarkers through mass spectrometry-based analysis of protein expression across various cancer types [2][4]. Group 1: Research Overview - The TPCPA covers 22 cancer types, including 18 solid tumors and 4 non-solid tumors, analyzing 999 primary tumor samples and quantifying 9,670 proteins [5][6]. - The study identifies multiple pan-cancer and specific protein biomarkers, potential therapeutic targets, and classifiers for cancer subtypes [2][6]. Group 2: Methodology and Findings - The research utilizes data-independent acquisition mass spectrometry (DIA-MS) to construct the proteome atlas, facilitating a comprehensive analysis of protein expression characteristics both inter- and intra-cancer types [4][6]. - The study highlights specific E3 ubiquitin ligases, such as HERC5 and RNF5, that are highly expressed in esophageal and liver cancers, respectively, as potential targets for protein-targeted degradation therapies [6]. Group 3: Cancer Subtype Classification - An analysis of 195 colorectal cancer cases led to the identification of consensus molecular subtypes (CMS) and two immune subtypes with prognostic value [7]. - A cancer subtype classifier based on 75 proteins was developed, demonstrating excellent performance (AUC greater than 0.98) in internal validation and four independent cohorts, including metastatic cancers [7]. Group 4: Data Accessibility - The research team has made all TPCPA data publicly available for free access and use through a dedicated portal [9].

Core Viewpoint - The research reveals a new mechanism by which psychological stress promotes pancreatic cancer through ALKBH5 deficiency and RNA transfer via extracellular vesicles, suggesting potential therapeutic strategies [3][9]. Group 1: Mechanism of Psychological Stress in Pancreatic Cancer - Psychological stress induces ALKBH5 deficiency, which leads to abnormal m6A modifications in RNA, promoting tumor innervation and progression of pancreatic ductal adenocarcinoma (PDAC) [3][6]. - The study demonstrates that pain perception and other stressors activate sympathetic nerves to release norepinephrine, downregulating ALKBH5 in tumor cells [6][9]. Group 2: Clinical Correlation and Potential Treatment - In PDAC patients, ALKBH5 levels are negatively correlated with tumor innervation and patient survival time [7]. - A natural flavonoid compound, fisetin, has been identified to inhibit neuronal uptake of extracellular vesicles carrying m6A-modified RNA, thereby suppressing excessive tumor innervation and cancer progression [7][9].