摘要：代谢功能障碍相关脂肪性肝炎（MASH）是一种影响全球数百万人的进展性肝病，早期常无明显症状，甚至在患者无症状的情况下悄然恶化。若未能及时干预，疾病可进一步发展为严重的肝硬化和肝癌，甚至危及生命，这使得寻找安全有效的治疗方案刻不容缓。当前，除瑞司美替罗（resm

编者按：代谢功能障碍相关脂肪性肝炎（MASH）是一种影响全球数百万人的进展性肝病，早期常无明显症状，甚至在患者无症状的情况下悄然恶化。若未能及时干预，疾病可进一步发展为严重的肝硬化和肝癌，甚至危及生命，这使得寻找安全有效的治疗方案刻不容缓。当前，除瑞司美替罗（resmetirom）外，在代谢领域广受关注的胰高糖素样肽-1受体激动剂（GLP-1 RA）司美格鲁肽（semaglutide）也获批MASH适应症，成为第二种获美国FDA批准的MASH疗法。随着新一轮MASH药物创新热潮的到来，创新药的研发需求尤为迫切。药明康德旗下的生物学业务平台（WuXi Biology）所建立的肝病研究平台正积极回应这一挑战，凭借多样化的临床前模型与高质量的科研服务，帮助全球合作伙伴将潜力候选药物高效推进至临床。以下案例显示，WuXi Biology建立的MASH临床前模型中，司美格鲁肽与替尔泊肽（tirzepatide）均展现出与临床试验一致的疗效，验证了该平台的科学价值与临床转化潜力。

MASH是代谢功能障碍相关脂肪性肝病（MASLD）的更严重阶段，已成为医学创新的重点领域。随着全球肥胖、胰岛素抵抗及代谢综合征人群的持续增加，数以百万计的患者正受到MASH的影响。若不及时治疗，MASH可能进展至肝硬化、肝癌等严重阶段。近年来，科学认知的不断深化与新疗法的涌现为改善MASH患者预后提供了前所未有的机遇。

在治疗探索领域，GLP-1 RA正展现出强大的潜力，不仅有望减轻肝脏炎症和纤维化，还能改善潜在的代谢风险。在一项3期临床试验中，司美格鲁肽相较安慰剂在脂肪性肝炎消退和纤维化改善方面均显示出显著优势。今年8月，该疗法正式获得美国FDA批准用于治疗MASH，成为首款在该适应症上获批的GLP-1 RA疗法，具有里程碑意义。与此同时，另一款双重GIP/GLP-1受体激动剂替尔泊肽也在一项2期临床试验中展现出突出的疗效，进一步印证了此类药物在MASH管理中的广阔前景。

为助力全球合作伙伴加速创新疗法研发，药明康德旗下WuXi Biology体内药理学团队建立了多种MASH的小鼠和大鼠模型，这些临床前模型已通过在临床中展现显著疗效的创新疗法（例如瑞司美替罗、司美格鲁肽和替尔泊肽）的验证，从而搭建起一座高效的转化桥梁，为全球合作伙伴开展严格的候选药物评估和创新研发提供有力支持。

由于GLP-1 RAs已知具有抑制食欲的作用，研究团队设立了严格的对照组，以区分饮食因素与药物在MASH治疗中的直接作用。在小鼠模型研究中，结果显示，与未接受治疗的小鼠相比，司美格鲁肽和替尔泊肽两种药物均显著改善了肝脏健康，减少了脂肪堆积和细胞损伤。与饮食匹配对照组相比，两种药物均表现出显著的抗纤维化效果。这些发现显示GLP-1 RAs在MASH治疗中的潜在益处不仅限于抑制食欲，其疗效还可能归因于药物本身对代谢的影响。实验室检测进一步印证了这一结论，结果显示，与饮食匹配对照组相比，司美格鲁肽和替尔泊肽均有助于降低肝脏脂肪、胆固醇、肝酶及血脂水平。

▲MASH小鼠模型中GLP-1 RA药物疗效的评估结果（图片来源：参考资料[1]）

研究团队还在MASH大鼠模型中测试了司美格鲁肽，并观察到一致的疗效，包括降低肝损伤评分、减轻纤维化，以及降低血液中关键肝酶和脂质水平。

研究还发现虽然使用同样的药物，但是在不同MASH模型中观察到的疗效结果也会有些许差异。这一现象进一步凸显出，采用多种动物模型进行全面评估能够更准确地理解药物的治疗机制并预测潜在获益。

▲MASH大鼠模型中GLP-1 RA药物疗效的评估结果（图片来源：参考资料[1]）

MASH之外，WuXi Biology建立了覆盖多种肝病、适用于小鼠和大鼠的丰富模型体系。这一能力已帮助全球合作伙伴在多种分子类型与靶点领域推进候选药物研发，其中许多项目已进入临床阶段，或获得监管批准。在药明康德“让天下没有难做的药，难治的病”的愿景激励下，团队融合多样化模型、严谨的研究设计与深入的数据分析，为全球合作伙伴提供可转化的研究洞见，加速潜力疗法的推进，以造福更多患者。

▲药明康德旗下生物学业务平台临床前肝病模型汇总（图片来源：参考资料[1]）

Driving Innovation — Advanced Preclinical MASH Models Paving the Way for the Next-Generation Treatments

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of liver disease affecting millions worldwide, often advances quietly with few or no symptoms in its early stages. Without timely intervention, it can lead to significant health complications, making the search for effective treatments increasingly important. Currently, apart from resmetirom, the GLP-1R agonist semaglutide, which has gained widespread attention in the metabolic field, has also been approved for MASH. A new wave of innovation in MASH drug development is underway, underscoring the urgent need for novel therapeutic solutions. As part of WuXi AppTec, WuXi Biology’s liver disease platform is designed to help meet this need, offering a broad portfolio of preclinical models and high-quality research services to support global partners in moving promising drug candidates from concept to clinic. In recent studies, both semaglutide and tirzepatide demonstrated efficacy in WuXi Biology’s MASH preclinical models, consistent with clinical trial outcomes and validating the platform’s scientific value and translational potential.

MASH, a more advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is drawing increasing attention as a key area for medical innovation. Closely linked to rising rates of obesity, insulin resistance, and metabolic syndrome, MASH affects millions of people worldwide. The disease can progress to serious conditions such as cirrhosis and hepatocellular carcinoma if left untreated. In recent years, the deepening scientific understanding and the emergence of new therapies have provided unprecedented opportunities to improve the prognosis of MASH patients.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have rapidly emerged as one of the most promising therapeutic classes for MASH, offering the potential not only to reduce liver inflammation and fibrosis but also to address the underlying metabolic risks driving disease progression. In a pivotal phase 3 trial, semaglutide delivered notable improvements in both steatohepatitis resolution and fibrosis compared to placebo. In August 2025, it received FDA approval as the first GLP-1 RA therapy for MASH, marking a historic milestone in the treatment of this challenging disease. Extending this momentum, tirzepatide—a dual GIP/GLP-1 receptor co-agonist—demonstrated significant efficacy in a phase 2 trial, further reinforcing the transformative potential of this therapeutic class in reshaping MASH management.

To accelerate the development of next-generation therapies,WuXi Biology’s in vivo pharmacology team has established and validated multiple mouse and rat models of MASH. These preclinical models have been benchmarked with approved and investigational drugs that have demonstrated clinical activity, including resmetirom, semaglutide, and tirzepatide, creating a robust translational bridge to support the rigorous evaluation of novel therapeutic candidates.

Because GLP-1 RA therapies are known to reduce appetite, the team established rigorous control groups to distinguish the impact of dietary factors from the direct effects of the drugs on MASH treatment. In a mouse model study, results showed that, compared with untreated mice, both semaglutide and tirzepatide significantly improved liver health by reducing fat accumulation and cellular damage. Moreover, both treatments demonstrated a significant reduction in fibrosis when compared with diet-matched controls.These findings highlight the potential benefits of GLP-1 RAs in treating MASH independent of diet.Laboratory tests also supported this observation, showing that compared to the diet-matched controls, both semaglutide and tirzepatide helped lower liver fat, cholesterol, liver enzymes, and blood lipid levels.

▲Efficacy evaluation of semaglutide and tirzepatide in the MASH Mouse Model (Source: Reference [1])

The team also tested semaglutide in a rat model of MASH and saw consistent benefits, including reduced liver damage scores, less fibrosis, and lower levels of key liver enzymes and fats in the blood.

The study also revealed efficacy variations across different models using the same drugs.Such variations further highlight the importance of using multiple animal models for comprehensive evaluation, to gain a deeper and more accurate understanding of the therapeutic mechanisms of drugs and predict their potential benefits.

▲Efficacy Assessment of Semaglutide in the MASH Rat Models (Source: Reference [1])

In addition to models for MASH, WuXi Biology’s liver disease platform established an extensive portfolio of models covering various liver diseases in both mice and rats.These capabilities have helped global partners advance drug candidates across a wide range of molecular modalities and targets, with many progressing into clinical development or receiving regulatory approval. Guided by WuXi AppTec’s vision—“Every drug can be made and every disease can be treated”—the team combines model diversity, rigorous study design, and in-depth data analysis to provide global partners with actionable insights that help advance promising therapies for patients.

▲WuXi Biology Liver Disease Models (Source: Reference [1])

参考资料:

[1] Emerging Role of GLP-1 Receptor Agonists for the Treatment of MASH. Retrieved August 13, 2025 from https://wuxibiology.com/resource/emerging-role-of-glp-1-receptor-agonists-for-the-treatment-of-mash/

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来源：健康诊疗科