FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2025 Jun 30;39(12):e70735. doi: 10.1096/fj.202500718R Q14.22025

Fibrogenic Gene Signature as Early Prediction for the Efficacy of Pharmacological Interventions for MASH-Associated Fibrosis

药物干预治疗MASH相关纤维化的疗效早期预测的纤维化基因特征signature 翻译改进

José A Inia^{1 2 3}, Martine C Morrison¹, Arianne van Koppen¹, Eveline Gart¹, Martien P M Caspers⁴, Aswin L Menke¹, Nicole Worms¹, Robert Kleemann¹, Lars Verschuren⁴, J Wouter Jukema^{2 3 5}, Hans M G Princen¹, Roeland Hanemaaijer¹, Anita M van den Hoek¹

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作者单位

¹ Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.

² Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.

³ Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands.

⁴ Department of Microbiology and Systems Biology, TNO, Leiden, the Netherlands.

⁵ Netherlands Heart Institute, Utrecht, the Netherlands.

DOI: 10.1096/fj.202500718R PMID: 40515541

摘要中英对照阅读

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) and associated liver fibrosis is rapidly increasing, while pharmacological treatment options remain limited. Despite great efforts in developing novel MASH therapeutics, many investigative therapeutics that reduced fibrosis in preclinical models ultimately failed in clinical trials. To this end, we explored the possibility of predicting the efficacy of therapeutics by evaluating chang... ...点击完成人机验证后继续浏览

代谢功能障碍相关脂肪性肝炎（MASH）及其相关的肝纤维化发病率正在迅速增加，而药理治疗选择仍然有限。尽管在开发新型 MASH 治疗方法方面付出了巨大努力，但许多在临床前模型中减少纤维化的研究疗法最终在临床试验中失败了。为此，我们探索了一种通过评估疾病早期发展阶段和病理变化显现之前纤维化基因特征表达的变化来预测治疗疗效的可能性。将 Ldlr-/-.Leiden 小鼠喂食高脂饮食（HFD）以诱导肥胖和 MASH。随后用不同具有已知效果（奥贝胆酸）或缺乏效果（岑西克利福考和吡格列酮）的疗法对小鼠进行为期 4 周的治疗，以研究它们的抗纤维化潜力。评估了预测在组织病理学纤维化发展之前促纤维化的进程的纤维生成基因特征表达。将这些预测与达到组织病理学纤维化终点的长期实验进行了比较。岑西克利福考和吡格列酮对 HFD 诱导的纤维化特征没有影响，表明这些治疗对活性纤维化过程无效果。一致地，在长期治疗研究中，岑西克利福考和吡格列酮对 HFD 引起的组织病理学测量的纤维化没有影响。相比之下，奥贝胆酸将纤维生成基因特征改善到比未经治疗的 HFD 对照组更健康的状态。这些早期基因表达变化与长期的组织学纤维化终点以及这些研究疗法的临床数据一致。这项研究突出了使用短期研究并通过应用纤维生成基因特征作为早期筛查工具来调查 MASH 相关纤维化的研究药物疗效的潜力。基于人类活性纤维化过程，这种签名在翻译小鼠模型中使用时可能允许快速筛选治疗方案或其组合。

关键词：MASH；MASLD；纤维化；基因特征；转录组学。

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期刊名：Faseb journal

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ISSN：0892-6638

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Fibrogenic Gene Signature as Early Prediction for the Efficacy of Pharmacological Interventions for MASH-Associated Fibrosis

药物干预治疗MASH相关纤维化的疗效早期预测的纤维化基因特征signature 翻译改进

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