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代谢性脂肪性肝炎（MASH，原NASH）全球患者超1亿，2024年resmetirom获批打破无药僵局，2025年8月司美格鲁肽（Wegovy）成为第二个获FDA批准的MASH治疗药物。本文梳理MASH核心发病机制及FXR激动剂、GLP-1R激动剂、脂肪生成抑制剂、FGF21类似物、联合疗法五大药物研发方向，并详解临床前研究中三种经典疾病小鼠模型（GAN饮食、HFD+CCl₄、MCD饮食）的构建方案与验证数据，同时介绍MASH相关靶点人源化小鼠模型资源。 MASH（代谢性脂肪性肝炎），这个让肝病领域又爱又恨的名字——爱它是因为市场空间巨大，恨它是因为研发失败率实在太高。不过好消息是，2024年resmetirom获批打破了"无药可用"的僵局，2025年8月司美格鲁肽（Wegovy）也正式获得FDA批准用于MASH治疗，标志着MASH药物研发进入了全新阶段。 今天小编就带大家梳理一下MASH的发病机制、药物研发格局，以及临床前研究中几种核心疾病小鼠模型的构建和验证数据。 什么是MASH 代谢性脂肪性肝病（metabolic dysfunction-associated steatohepatitis，MASH，原称为NASH）是一种与代谢紊乱密切相关的慢性肝脏疾病。其主要病理特征包括：脂质过度积累（脂肪变性）、免疫细胞浸润（炎症）和肝星状细胞活化介导的纤维化。该疾病不仅局限于肝脏，还可能引发代谢、心血管、消化、内分泌、免疫及肾脏等全身器官损伤，与肥胖、II型糖尿病、心血管疾病等代谢性疾病都密切相关 [1-3]。 目前，在全球范围，已有超1亿例MASH患者。我们迫切需要阐明潜在的治疗靶点并开发有效的药物治疗方法 [4]。 图1. MASLD与MASH的系统性影响 [5]。 MASH治疗药物的研发进展 MASH的治疗仍面临挑战。尽管生活方式干预（如饮食控制和运动）是基础治疗手段，但其长期依从性较低。靶向代谢通路的药物研发已取得重要突破： FDA于2024年3月批准瑞司美替罗（resmetirom）作为首个获批的MASH治疗药物 ，通过激活甲状腺激素受体β（THR-β）改善肝脏脂肪代谢和炎症； 2025年8月，FDA批准Wegovy（司美格鲁肽2.4mg）用于治疗伴中度至重度纤维化的非肝硬化MASH成人患者 ，成为第二个获批的MASH治疗药物。此外，FGF21类似物、FXR激动剂等新型疗法也在临床试验中展现出显著疗效。以下是几类MASH药物的研发进展： · 法尼醇X受体（FXR）激动剂 FXR主要在肝脏和肠道中表达，其内源性配体为胆汁酸（bile acid，BA）。作为BAs稳态、脂质和葡萄糖代谢的关键调节因子，FXR激动剂正在不断开发并尝试治疗MAFLD。 代表性药物奥贝胆酸是一种口服FXR激动剂，该药于2016年5月被FDA批准用于治疗原发性胆汁性胆管炎（PBC）之后，迅速进入MASH的III期临床，但因安全性风险、疗效不足等以失败告终。尽管奥贝胆酸在MASH领域折戟，但FXR激动剂的研发并未停滞。国内企业如拓臻生物开发的TERN-101、歌礼制药的ASC42等新型FXR激动剂已进入临床试验阶段。 · 胰高血糖素样肽-1受体（GLP-1R）激动剂 GLP-1R激动剂能够刺激胰岛素的分泌、降低胰高血糖素的分泌、延缓胃排空以及减少食欲，从而有助于体重管理，是目前常用的治疗2型糖尿病的药物，同时也被视为潜在的MASH治疗药物。 司美格鲁肽（Semaglutide）作为GLP-1R激动剂的代表药物，已在多项临床试验中展现出对MASH的显著疗效。在NEJM发表的ESSENCE III期试验中，每周2.4 mg剂量的司美格鲁肽治疗72周后，62.9%的患者实现了脂肪性肝炎缓解且肝纤维化未恶化，而安慰剂组仅为34.3%。此外，36.8%的司美格鲁肽组患者肝纤维化程度得到改善，显著高于安慰剂组的22.4%。该研究还发现，司美格鲁肽可带来平均10.5%的体重减轻，并改善肝酶水平及非侵入性肝纤维化标志物。基于ESSENCE试验数据，FDA于2025年8月15日批准Wegovy（司美格鲁肽2.4mg注射剂）用于治疗伴中度至重度肝纤维化的非肝硬化MASH成人患者。 · 脂肪生成抑制剂 肝脏中从头脂肪生成（DNL）过度会导致总胆固醇（TG）积累和脂肪毒性，从而导致肝脏脂肪变性。由碳水化合物底物参与脂肪酸生物合成的关键酶包括柠檬酸ATP合酶（ACLY）、乙酰辅酶A（乙酰-CoA）羧化酶（ACC）和脂肪酸合成酶（FASN）等。ACLY抑制剂和单酰基甘油酰基转移酶2（MGAT2）抑制剂具有治疗MASH的潜力。 · FGF类似物 FGF21是FGF超家族的非典型成员，在调节能量平衡以及葡萄糖和脂质平衡方面发挥着重要作用。efruxifermin是一种分化型Fc-FGF21融合蛋白，旨在模拟原生FGF21的平衡生物活性。其HARMONY Phase 2b研究96周数据显示，在非肝硬化MASH伴中度至重度纤维化（F2/F3）患者中，纤维化和MASH均取得统计学显著改善。目前efruxifermin的III期临床项目（SYNCHRONY）正在推进中。 · 联合疗法 针对多靶点的联合疗法已成为研究热点。相较于单一疗法，联合疗法通过协同作用机制可提升疗效，并通过降低单药剂量减少副作用风险。例如ACC抑制剂与DGAT2抑制剂的联合应用、几种FXR激动剂的联合疗法、与抗糖尿病药物联合使用等。 图2. 在小鼠MASH模型中，联合应用肝脏ACLY抑制剂贝哌地酸与GLP-1R激动剂利拉鲁肽 ，可减少肝脏脂肪变性、肝细胞气球样变及肝纤维化 [7] 动物模型 小鼠模型在MASH研究中扮演着至关重要的角色。常用的代表性动物模型包括高脂饮食（High-fat diet, HFD）联合四氯化碳（CCl₄）诱导的疾病小鼠模型、胆碱缺乏饮食诱导的模型、Gubra Amylin（GAN）饮食诱导模型以及基于人源化小鼠模型构建的MASH疾病模型。 南模生物代谢/心血管疾病评价平台拥有多种经典的代谢模型，并具有丰富的模型开发及药理药效分析经验，可提供成品模型、模型定制、药效评价等一站式临床前CRO服务。 01 GAN饮食诱导的MASH模型 GAN（Gubra-Amylin NASH）饮食是一种经过改良、无反式脂肪的高脂高胆固醇高果糖饲料，其诱导的MASH动物模型更好地模拟了人类疾病的发生，在生理、代谢和组织病理学方面有良好的转化性。 图3. GAN饮食诱导（40% fat+25% fructose in calorie+2% cholesterol (g/g) for 20 weeks）C57BL/6小鼠MASH模型构建。 A. 小鼠体重曲线；B. 小鼠肝体积比变化情况；C. GAN造模后小鼠各项血生化指标检测。(_** P<0.001, _ P<0.05) 图4. 司美格鲁肽（Semeglutide, s.c., QD, 30 days）使GAN诱导的MASH小鼠症状显著改善。 A. 小鼠体重曲线；B. 小鼠肝体比变化情况；C. 小鼠各项血生化指标；D. 小鼠肝脏切片染色（左：Masson染色；右：H&E染色）；E. 小鼠肝脏胶原沉积分数; F. 小鼠肝脏NAS分数。（*** P<0.001, ** P<0.01, * P<0.05） 02 HFD+CCl₄诱导的MASH模型 HFD+CCl₄模型的构建由两部分组成：首先是高脂饮食（High-Fat Diet，HFD）单独诱导肝脂肪变性以及炎症反应，然后在HFD的基础上用CCl₄诱导肝纤维化。 图5. HFD+CCl₄诱导 (60% high fat diet for 8~10weeks+10% CCl₄) C57BL/6小鼠MASH模型构建。 A. 小鼠体重曲线；B. 小鼠体重变化情况。 图6. OCA (30mpk, P.O., QD) 给药30天后，HFD+CCl₄诱导的MASH小鼠肝炎症状有显著的改善。 A. 小鼠体重曲线；B. 小鼠体重变化率；C. 小鼠各项血生化指标；D. 肝脏切片染色 (左：Masson染色；右：H&E染色)；E. 胶原沉积分数; F. 肝脏NAS分数。（*** P<0.001, ** P<0.01, * P<0.05） 03 MCD饮食诱导的MASH模型 甲硫氨酸和胆碱缺乏饮食（Methionine-Choline-Deficient Diet，MCD）含有21％脂肪，63％蔗糖为主的碳水化合物，缺乏胆碱和甲硫氨酸，该饮食方案可通过引起肝脏脂类的输出障碍从而驱动肝损伤。MCD模型在较短的时间内即可表现出MASH和肝纤维化。 图7. MCD诱导 (MCD diet for 7 days) C57BL/6与FVB/N小鼠MASH模型构建。 A. 小鼠体重曲线; B. 小鼠体重变化情况。C. 小鼠各项血生化指标。（_** P<0.001, _ P<0.05） 图8. MCD诱导的MASH小鼠肝部病理变化。 A. 小鼠肝脏Masson染色; B. 小鼠肝脏胶原沉积分数; C. 小鼠肝脏H&E染色; D. 小鼠肝脏NAS分数。（_** P<0.001, _ P<0.05） MASH相关靶点人源化小鼠模型 MASH药物研发领域正经历快速发展，靶点探索、新型分子实体开发以及临床研究引领的多维度创新共同推动着该领域不断突破。除上述模型外，南模生物还可提供MASH相关靶点人源化小鼠模型，助力新药研发。 图9. 南模生物MASH相关靶点人源化小鼠模型 参考文献 [1] GOLDBERG D, DITAH IC, SAEIAN K, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation[J]. Gastroenterology, 2017, 152(5): 1090-1099.e1. [2] Petta S, Targher G, Romeo S, et al. The first MASH drug therapy on the horizon: Current perspectives of resmetirom. Liver Int. 2024 Jul;44(7):1526-1536. [3] Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J. Hepatol. 69, 896–904 (2018). [4] Gaspar-Silva F, Trigo D, Magalhaes J. Ageing in the brain: mechanisms and rejuvenating strategies. Cell Mol Life Sci. 2023 Jun 24;80(7):190. [5] Sandireddy R, Sakthivel S, Gupta P, et al. Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases. Front Cell Dev Biol. 2024 Jul 16;12:1433857. [6] Xu X, Poulsen KL, Wu L, et al. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther. 2022 Aug 13;7(1):287. [7] Desjardins EM, Wu J, Lavoie DCT, et al. Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice. Cell Rep Med. 2023 Sep 19;4(9):101193. 关于我们 上海南方模式生物科技股份有限公司（Shanghai Model Organisms Center, Inc.，简称"南模生物"），成立于2000年9月，是一家上交所科创板上市高科技生物公司（股票代码：688265），始终以编辑基因、解码生命为己任，专注于模式生物领域，打造了以基因修饰动物模型研发为核心，涵盖多物种模型构建、饲养繁育、表型分析、药物临床前评价等多个技术平台，致力于为全球高校、科研院所、制药企业等客户提供全方位、一体化的基因修饰动物模型产品解决方案。 微信公众号「南模生物 SMOC」在线咨询

Metabolic dysfunction-associated steatohepatitis (MASH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are progressive chronic liver diseases linked to abnormal bile-acid metabolism. Although these diseases differ in origin, they all lead to a similar outcome: abnormal hepatic accumulation of bile acids and liver injury. The farnesoid X receptor (FXR) is a protein inside cells that acts as a transcription factor, functioning primarily as the body's sensor for bile acids. Delivering an FXR agonist—a molecule that activates FXR—is one of the strategies for treating these diseases, by reducing the build-up of bile acids. In the search for effective therapies, drug developers have long pursued a drug-delivery strategy centered on long half-life and sustained exposure. For example, over the past two decades, nearly all of the 20-plus FXR agonists that have entered clinical trials have been long-acting. However, many of the body's physiological processes are inherently rhythmic and pulsatile, meaning that long-acting drugs may be mismatched with the body's natural rhythms—a condition that may gradually impair receptor responsiveness. Now, researchers led by H. Eric Xu and LI Jia from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences have proposed what they call the "first principle of drug design"—designing drugs whose delivery mimics the body's physiology—to create a new type of FXR agonist. By using pulsatile activation to mimic the physiological, dynamic fluctuations of endogenous bile acids, they have designed and synthesized a non-bile-acid FXR agonist—a novel drug candidate, Linafexor (CS0159). The study was published in Nature on June 10. The researchers designed Linafexor as a "quick-in, quick-out" molecule that engages its target in pulses—similar to pressing a switch then releasing it. Once in the body, it is rapidly metabolized and cleared, achieving pulsatile FXR activation synchronized with the natural fluctuations of bile acids. The receptor is briefly and strongly activated after each dose, then falls back and is allowed to recover, avoiding what the researchers describe as "chronic fatigue," which they propose underlies the gradual loss of receptor responsiveness. Linafexor exhibited a half-maximal effective concentration (EC50) of 0.35 nM, indicating very high potency, on par with the long-acting tropifexor and roughly 800 times more potent than obeticholic acid. The researchers solved the crystal structure of the drug bound to FXR and revealed that it fits well into the ligand-binding pocket. Compared with the clinically tested tropifexor, the two adopt almost identical binding poses in the pocket, confirming Linafexor's efficient binding at the molecular level. Unlike long-acting FXR agonists with half-lives of 14-24 hours, Linafexor was designed for rapid clearance. In preclinical species, its half-life is under one hour. Distribution studies showed that after dosing, Linafexor concentrated where it was needed most: the liver, small intestine, and stomach. It was cleared from all tissues within 24 hours, achieving intended pulsatile exposure synchronized with bile-acid rhythms. In MASH, liver fibrosis, PBC, and PSC animal models, Linafexor significantly improved markers of liver injury, inflammation, and fibrosis. Notably, when the researchers switched the identical Linafexor molecule from pulsatile to continuous dosing, the animals developed severe systemic toxicity; once-daily pulsatile dosing, by contrast, was safe and effective. This finding suggests that the duration of receptor activation, rather than molecular structure alone, may be a key determinant of a drug's safety and efficacy. Associated with this finding, the researchers proposed the concept of "bile-acid resistance," analogous to insulin resistance, wherein chronic, excessive signaling desensitizes the receptor and disrupts the signaling pathway. In the Phase I trial completed in the United States, the human data closely matched the researchers' design expectations. After oral dosing, Linafexor was rapidly absorbed and cleared, with a half-life again under one hour. The drug precisely "lit up" its target: FGF19, a marker of FXR activation, rose markedly, while C4, a marker of bile-acid synthesis, fell significantly. They both returned to baseline within 24 hours, recapitulating in humans the pulsatile activation pattern seen in animal models. Safety has long been the Achilles' heel of FXR-class drugs. Yet across all single- and multiple-ascending-dose groups in this Phase I study, the Linafexor groups showed no drug-related adverse events, in contrast with some FXR agonists. Linafexor has already completed Phase II clinical trials and has now entered Phase III trials, with preliminary data showing efficacy and safety in both PBC and MASH. This study proposes a new principle for drug discovery: The design of drugs should take into account natural signaling rhythms to reduce the risk of toxicity caused by sustained drug delivery. This principle may be particularly applicable to physiological processes such as hormone signaling, immune regulation, and circadian metabolism, all of which depend on rhythmic rather than sustained signaling. Figure |Crystal structure of Linafexor bound to FXR. Left: Linafexor (yellow) docked into the binding pocket of FXR (green), interacting with multiple residues; Right: Linafexor (yellow) and tropifexor (blue) adopt highly overlapping binding poses DOI: 10.1038/s41586-026-10633-1 Link: https://www.nature.com/articles/s41586-026-10633-1 Keywords: FXR, bile-acid-related liver diseases, pulsatile activation, Linafexor, CS0159, drug design Contact: DIAO Wentong Shanghai Institute of Materia Medica E-mail: diaowentong@simm.ac.cn