Zhang Xiang, Lau Harry Cheuk-Hay, Yu Jun
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
Pharmacol Rev. 2025 Mar;77(2):100018. doi: 10.1016/j.pharmr.2024.100018. Epub 2024 Nov 22.
Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.
代谢功能障碍相关脂肪性肝病（MASLD；原称非酒精性脂肪性肝病）是一种慢性肝病，全球有超过十亿人受其影响。MASLD可逐渐发展为更严重的肝脏病变，包括代谢功能障碍相关脂肪性肝炎（MASH）、肝硬化和肝癌。值得注意的是，尽管这是一个全球性的健康问题，但针对MASLD及其相关疾病的治疗选择非常有限。虽然一种甲状腺激素受体激动剂（resmetirom）最近被批准用于治疗MASH，但控制这些疾病的其他努力仍不尽人意。鉴于预计MASLD和MASH的发病率将会上升，迫切需要开发针对这些常见肝病的新颖有效的治疗策略。在本文中，介绍了MASLD和MASH的致病机制，包括胰岛素抵抗、核受体信号失调以及遗传风险因素（如含patatin样磷脂酶结构域3和羟类固醇17-β脱氢酶-13）。然后探讨了针对MASH的各种治疗干预措施，包括已批准的药物（resmetirom）、目前正在临床试验中的药物（如胰高血糖素样肽1受体激动剂、成纤维细胞生长因子21类似物和PPAR激动剂）以及先前试验中失败的药物（如奥贝胆酸和硬脂酰辅酶A去饱和酶1拮抗剂）。此外，鉴于肠道微生物群在MASLD中的作用日益受到认可，本文阐明了MASLD发展过程中肠道微生物群的变化及微生物机制。进一步探索了针对肠道微生物群的治疗方法（如饮食干预和益生菌）来治疗MASLD及其相关疾病。随着对多方面致病机制的更好理解，极大地促进了针对MASLD和MASH根本原因的创新疗法的开发。缓解MASH并实现更好患者预后的可能性指日可待。重要声明：代谢功能障碍相关脂肪性肝病（MASLD）是全球最常见的慢性肝病，它可进展为更严重的病变，包括脂肪性肝炎、肝硬化和肝癌。对这些疾病致病机制的更好理解促进了创新治疗策略的开发。此外，越来越多的证据表明肠道微生物群在MASLD及其相关疾病的发病机制中起关键作用。未来针对肠道微生物群来缓解MASLD在临床上可能是可行的。
