The treatment of metabolic dysfunction-associated steatohepatitis (MASH) has proven challenging, with many compounds failing during development for various reasons. However, with the recent accelerated approval of resmetirom by the US Food and Drug Administration for the treatment of individuals with fibrotic MASH,¹ there is renewed enthusiasm in the field. MASH pathophysiology is complex, and progressive disease results from an imbalance between the driving metabolic inflammatory mechanisms (many of which are extrahepatic; eg, the dysfunctional adipose tissue) and intrahepatic defence and repair mechanisms.² Many of the compounds currently considered to be the most promising mainly improve the cardiometabolic environment, subsequently (with or without additional direct intrahepatic effects) improving MASH. Many drugs targeting specific intrahepatic metabolic or fibroinflammatory mechanisms have proven unsuccessful in clinical trials, despite preclinical evidence.³ Resmetirom, a liver-targeted thyroid hormone β receptor agonist, showed that a more isolated liver-directed approach, with little or no effect on the extrahepatic drivers of MASH, is also capable of not only improving MASH but inducing the regression of fibrosis.¹

中文翻译：

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扩大代谢功能障碍相关脂肪性肝炎的武器库


代谢功能障碍相关脂肪性肝炎 （MASH） 的治疗已被证明具有挑战性，许多化合物在开发过程中由于各种原因而失败。然而，随着美国食品药品监督管理局最近加速批准 resmetirom 用于治疗纤维化 MASH 患者，¹ 该领域重新燃起了热情。MASH 的病理生理学很复杂，疾病进展是由于驱动代谢炎症机制（其中许多是肝外的，例如，功能失调的脂肪组织）和肝内防御和修复机制之间的不平衡引起的。² 目前被认为是最有前途的许多化合物主要改善心脏代谢环境，随后（有或没有额外的直接肝内影响）改善 MASH。尽管有临床前证据，但许多靶向特定肝内代谢或纤维化炎症机制的药物在临床试验中已被证明不成功。³ Resmetirom 是一种肝脏靶向甲状腺激素β受体激动剂，表明一种更孤立的肝脏导向方法，对 MASH 的肝外驱动因素影响很小或没有影响，也不仅能够改善 MASH 而且能够诱导纤维化消退。¹