撰文丨王聪 编辑丨王多鱼 排版丨水成文 从 代谢功能障碍相关脂肪性肝病 （MASLD） 发展到 代谢功能障碍相关脂肪性肝炎 （MASH） 的过程，会导致肝脏迅速且往往是不可逆的损伤，这凸显了创新 治疗策略的迫切需求。 2026 年 3 月 2 日， 上海交通大学医学院附属第六人民医院转化医学中心/上海市糖尿病重点实验室 贾伟 教授 、 郑晓皎 教授团队 （ 唐雅珺 、 况俊良 为论文 共同第一作者） 在 Cell Metabolism 期刊发表了题为： Targeting microbiota-generated acetaldehyde to prevent progression of metabolic dysfunction- associated steatotic liver disease 的研究论文。 该研究表明， 高糖饮食 下， 肠道微生物 会 产生 内源性乙醛 ，从而在没有酒精摄入的情况下损伤肝脏， 加速 MASLD 向 MASH 的发展。研究团队进一步发现 并通过合成生物学改造了能够清除乙醛的益生菌，在临床前模型中 有效减轻了肝纤维化和炎症。 这项研究不仅 突破 了肝病发病机制的认知 界 ...

Core Viewpoint - The study highlights that Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) accelerates the progression and metastasis of Pancreatic Ductal Adenocarcinoma (PDAC) through the macrophage migration inhibitory factor-CD44 axis [5][8]. Group 1: Research Findings - MASLD significantly increases the overall risk of PDAC, with a risk ratio of 3.48 observed in the population with MASLD [7]. - A strong correlation between MASLD and liver metastasis was confirmed in clinical cohort studies, with an odds ratio of 7.06 [7]. - Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and the formation of cell adhesion plaques in metastatic liver tissue [7]. Group 2: Mechanism and Implications - MASLD-induced MIF secretion promotes the migration, stemness, and adhesion of CD44-positive PDAC cells [8]. - Targeting MIF through genetic means or using the MIF isomerase inhibitor IPG1576 significantly reduced liver metastasis in preclinical models [8]. - The study emphasizes the MIF-CD44 signaling axis as a promising therapeutic target and the importance of developing personalized treatment plans for PDAC patients with concurrent MASLD [8].

Core Insights - The study indicates that Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a diurnal disease influenced by multi-system insulin resistance and reduced insulin availability at night [3][9] - The severity of MASLD and related metabolic disorders exhibits significant diurnal fluctuations, with nighttime being the period of most severe metabolic issues, providing new insights for optimal timing of diet, exercise, and medication for patients [3][12] Summary by Sections - **Introduction to MASLD**: MASLD affects approximately 40% of the global population and is closely linked to obesity and insulin resistance (IR). It is characterized by excessive triglyceride (TAG) accumulation in liver cells, which can progress to Metabolic Dysfunction-Associated Steatotic Hepatitis (MASH), cirrhosis, and hepatocellular carcinoma [5] - **Mechanisms of MASLD**: The pathogenesis of MASLD depends on the imbalance between lipid influx and synthesis versus clearance in the liver. TAG in the liver originates from fatty acid esterification, which can come from fat tissue breakdown, dietary intake, or de novo lipogenesis (DNL) [5] - **Circadian Influence on Metabolism**: Preclinical models show that liver metabolic homeostasis is strongly influenced by biological clocks, which synchronize physiological functions and behaviors over a 24-hour cycle. Disruption of these rhythms can lead to adverse metabolic outcomes, including liver steatosis [6] - **Research Findings**: The study analyzed diurnal metabolic phenotypes in MASLD patients and overweight controls using advanced stable isotope techniques. Key findings include significant nighttime metabolic dysfunction in MASLD, with activated pathogenic pathways such as hepatic and peripheral insulin resistance, DNL, and systemic NEFA exposure [7][9] - **Persistent Nighttime Dysfunction**: Even after weight loss and reduction of liver fat, nighttime metabolic dysfunction persists, suggesting it may be a primary driver of steatosis [8] - **New Treatment Strategies**: The research suggests a new therapeutic approach—time therapy. This includes scheduling most caloric intake during the day when insulin sensitivity is higher, exercising during less favorable metabolic periods, and adjusting medication timing based on the disease's circadian characteristics to maximize efficacy [12]

Core Viewpoint - The study highlights the role of hepatic GPR110 in the sex-specific development of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASH), suggesting it as a potential target for female-specific therapies [4][8]. Group 1: Research Findings - GPR110 is identified as a liver-specific G protein-coupled receptor (GPCR) that is closely related to MASH in a sex-specific manner [6]. - The knockout of the Gpr110 gene in liver cells protects female mice from MASH, while having no effect on male mice [6]. - The variant rs937057 T>C of GPR110 is associated with a higher prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in women [6]. Group 2: Mechanism of Action - GPR110 couples with Gαs to activate protein kinase A (PKA), which induces phosphorylation of NFAT2, inhibiting its nuclear translocation and transcriptional activity, leading to suppression of Esr1 transcription in liver cells [6][8]. - Reducing Gpr110 expression in liver cells improves the liver pathology in female MASH mice, while knocking down estrogen receptor α (Esr1) negates this improvement [6]. Group 3: Implications for Therapy - The findings suggest that inhibiting GPR110 may represent a gender-specific therapeutic approach for MASH, emphasizing the need for targeted treatments based on sex differences [4][8].

Core Viewpoint - The article discusses the discovery of a novel membraneless organelle called Lipid-induced granule (LIG) in hepatocytes, which is induced by lipid accumulation and has implications for understanding liver fibrosis and potential intervention targets for fatty liver disease [3][9]. Group 1: Discovery and Characteristics of LIG - A new type of membraneless organelle, named Lipid-induced granule (LIG), has been identified in hepatocytes, revealing its characteristics, formation, and function [3]. - LIG is formed through the liquid-liquid phase separation (LLPS) of the DDX49 protein, which is induced by lipid metabolites, particularly arachidonic acid [10]. Group 2: Mechanism of Action - LIG plays a role in inhibiting the progression of metabolic dysfunction-associated fatty liver disease (MASLD) by feedback inhibition of the pro-fibrotic liver factor TIMP2 [10]. - The mechanism involves the recruitment of m5C-modified Timp2 mRNA and its reader YBX1 to LIG, which suppresses the translation of Timp2 mRNA, thereby inhibiting liver fibrosis [7][10]. Group 3: Clinical Relevance - The presence of LIG has been identified in human MASLD livers, and its abundance is negatively correlated with the progression of fibrosis [8]. - The global prevalence of MASLD is estimated to be 30% among adults, with its severe form, MASH, leading to liver fibrosis and significant health risks [6].

Core Insights - The article discusses the increasing global health issue of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), previously known as Non-Alcoholic Fatty Liver Disease (NAFLD), highlighting its progression to Metabolic Dysfunction-Associated Steatohepatitis (MASH) and the associated risks of morbidity and mortality [1][4]. Group 1: Research Findings - A recent study published in Cell Reports Medicine identified blood metabolic panels that can detect significant fibrosis and inflammation in MASLD patients, revealing key metabolites such as Guanidinoacetic Acid (GAA) and Decanoic Acid (SA) that show therapeutic potential in mouse models [2][5]. - The research involved 293 participants across three independent cohorts, utilizing machine learning techniques to develop a non-invasive diagnostic model for detecting significant fibrosis (≥F2) and moderate to severe inflammation (≥I2) [4]. - The area under the receiver operating characteristic curve (AUROC) for fibrosis detection reached 0.928, 0.829, and 0.806 in the discovery, validation cohort 1, and validation cohort 2, respectively, outperforming existing indices like FIB-4 and APRI [4]. Group 2: Implications for Diagnosis and Treatment - The study's findings provide a systematic exploration of the key metabolic features of MASLD, paving the way for new non-invasive diagnostic and treatment strategies [7]. - The identified metabolites GAA and SA can improve liver fat deposition, inflammation, and fibrosis through dual mechanisms of "regulating lipid metabolism" and "promoting inflammation resolution," indicating their potential in advancing MASLD management [5].

Core Insights - The study published by Yale University reveals a significant association between the consumption of sweetened beverages (both sugary and artificially sweetened) and adverse liver health outcomes, indicating that daily intake of these beverages increases the risk of metabolic dysfunction-related fatty liver disease (MASLD), severe liver disease, and chronic liver disease mortality [2][4]. Group 1: Study Overview - The research utilized data from the UK Biobank, involving 173,840 participants aged 40-69, and applied Cox proportional hazards regression models to analyze the relationship between sweetened beverage consumption and liver health outcomes [3]. - At baseline, 14.2% of participants consumed at least one sugary drink daily, while 10.8% consumed at least one artificially sweetened drink daily, with one serving defined as 250mL [3]. Group 2: Findings on Beverage Consumption - Each additional serving of sugary beverages per day was associated with a 10% increase in MASLD risk, a 21% increase in cirrhosis risk, an 18% increase in severe liver disease risk, and a 37% increase in chronic liver disease mortality risk [4]. - For artificially sweetened beverages, each additional serving per day correlated with a 15% increase in MASLD risk, a 14% increase in severe liver disease risk, and a 41% increase in chronic liver disease mortality risk [4]. Group 3: Health Improvement Potential - Reducing sweetened beverage intake may significantly improve liver health; substituting one serving of sugary drinks with tea or coffee is linked to a 10%-32% reduction in risks associated with MASLD, cirrhosis, severe liver disease, and chronic liver disease mortality [5]. - Similarly, replacing one serving of artificially sweetened beverages with tea or coffee is associated with a 14%-34% reduction in the same health risks [5]. Group 4: Protein Signatures and Health Risks - The study identified specific proteomic signatures associated with sweetened beverage consumption that correlate with increased risks of MASLD, cirrhosis, severe liver disease, and chronic liver disease mortality [5]. - For sugary beverages, each standard deviation increase in related proteomic features was linked to a 65% increase in MASLD risk, a 52% increase in cirrhosis risk, a 111% increase in severe liver disease risk, and a 53% increase in chronic liver disease mortality risk [5]. - For artificially sweetened beverages, the corresponding increases were 96% for MASLD, 71% for cirrhosis, 114% for severe liver disease, and 442% for chronic liver disease mortality [5]. Group 5: Implications for Dietary Recommendations - The findings underscore the importance of understanding how sweetened beverages impact liver health and suggest the need for personalized dietary recommendations to reduce the intake of these beverages to improve liver health and lower the risk of severe complications related to liver disease [6].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 近年来，研究人员创造了各种类器官以模拟人体器官的功能，然而，一直难以构建出能够增殖且功能完备的 肝脏类器官 。这是因为，在实验室条件下， 肝脏中 的主要细胞肝细胞会发生 胆管化生，转变为胆管细胞样细胞，以平衡细胞功能和增殖之间的能量消耗，这导致肝细胞的功能最多只能维持 1-2 周。 2025 年 4 月 16 日， 庆应义塾大学医学院 佐藤俊朗 教授团队在国际顶尖学术期刊 Nature 上发表了题为 ： Generation of human adult hepatocyte organoids with metabolic functions 的研究论文。 该研究从直接取自人类患者的冷冻保存的成人肝细胞中培养出了 具有代谢功能的成人肝细胞类器官 。研究团队使用 参与炎症反应的信号蛋白 抑瘤素M （ Oncostatin-M，OSM ） 进行处理，使得肝细胞类器官的增殖量达到了百万倍，这与之前研究中的肝细胞几乎不生长的情况形成了鲜明对比。这些肝细胞类器官 持续生长了三个月，并且在半年内仍保持分化能力。这些肝细胞类器官为肝脏疾病的建模和治疗提供了新平台。 在这项最新研究中 ...