中国科学院上海药物研究所徐华强研究团队宣布他们提出了一种用于胆酸相关性肝病的一流搏动性FXR激动剂。该项研究成果发表在2026年6月10日出版的《自然》上。

在这里，研究组报告了一种第一性原理的药物设计策略，使药代动力学与生理信号周期保持一致。该课题组研究人员开发了linafexor，一种有效的farnesoid X受体（FXR）的非胆汁酸激动剂；它被设计用于快速的全身清除，从而使反映内源性胆汁酸动态的脉动受体激活。利那福在代谢功能障碍相关的脂肪性肝炎、肝纤维化、原发性胆道性胆管炎和原发性硬化性胆管炎的多种临床前模型中均具有良好的疗效。

转录组学分析显示，与长效FXR激动剂不同，利那韦可保留循环FXR信号，避免受体下调并防止广泛的转录失调。直接操纵递送模式表明，持续的FXR激活-独立于化合物身份-诱导严重的毒性，建立激活时间作为治疗指数的决定因素。在1期临床研究（ClinicalTrials.gov; NCT05082779）中，每天给药一次利那韦可产生短暂的FXR通路作用，其标志是：(1)诱导FGF19，一种胆汁酸反馈调节的关键内分泌介质；(2)抑制C4（一种反映肝胆汁酸合成的中间体），无治疗相关不良事件。总之，这些发现确定了脉动性FXR激活作为一种机制基础和临床可翻译的策略，并确立了利那韦作为胆汁酸相关肝脏疾病的一流治疗药物。

据介绍，核受体是代谢的中枢调节因子，然而，强制持续激活核受体的治疗策略经常导致疗效降低和不可接受的毒性。

附：英文原文

Title: A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

Author: Zang, Yi, Shi, Jingjing, Zhao, Guanguan, Tang, Bixi, Liu, Mingliang, Yao, Benqiang, Wang, Gaihong, Pan, Hualing, Yang, Shengsheng, Deng, Rong, Zhao, Yishuang, Zhang, Zhenwei, Guo, Hao-Ran, Sun, Dan-Dan, Wang, Hanlin, Gao, Lixin, Yu, Jinghua, Diao, Xingxing, Li, Yong, Li, Jia, Xu, H. Eric

Issue&Volume: 2026-06-10

Abstract: Nuclear receptors are central regulators of metabolism1, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR)2; it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics3,4,5. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis6, liver fibrosis7, primary biliary cholangitis and primary sclerosing cholangitis8,9. Transcriptomic analyses reveal that, unlike long-acting FXR agonists10,11, linafexor preserves cyclic FXR signalling, avoids receptor downregulation and prevents broad transcriptional dysregulation. Direct manipulation of delivery patterns demonstrates that sustained FXR activation—independent of compound identity—induces severe toxicity, establishing activation duration as a determinant of therapeutic index. In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF1912,13,14, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C415, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid–related liver diseases.

DOI: 10.1038/s41586-026-10633-1

Source: https://www.nature.com/articles/s41586-026-10633-1