A Long-Acting Farnesoid X Receptor (FXR) Agonist Prevents Fibrosis.

IF 5.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomolecules Pub Date : 2026-10-03 DOI:10.3390/biom16101443

Ashrafi Sultana, Grace Bybee, Anup S Pathania, Weimin Wang, Nam Thai Hoang Le, Brandon W Hanson, Christopher D Bauer, Deanna D Mosley, Howard E Gendelman, Samuel M Cohen, Todd A Wyatt, Larisa Y Poluektova, Benson J Edagwa, Natalia A Osna

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Abstract

Despite effective vaccines and antiviral therapies, patients with chronic hepatitis B (CHB) remain at risk of developing progressive liver fibrosis and cirrhosis. Vonafexor (VON), a second-generation synthetic non-steroidal, non-bile acid farnesoid X receptor agonist, has been shown to prevent liver fibrosis and target the HBV cccDNA reservoir. However, adherence to daily oral therapy is an established barrier to successful treatment of chronic infections. To overcome this barrier, VON was transformed into a long-acting (LA) prodrug nanosuspension. The LA prodrug formulation suppressed αSMA, TGFβ, and Col1A1 gene expression in the LX2 hepatic stellate cell line. The formulation was well tolerated and prevented liver and lung damage in a carbon tetrachloride-induced chronic liver injury model. The promising preclinical data support further development of LA VON prodrugs as potential treatments for liver and lung fibrosis.

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一种长效法内酯X受体（FXR）激动剂预防纤维化

尽管有有效的疫苗和抗病毒治疗，慢性乙型肝炎（CHB）患者仍有发展为进行性肝纤维化和肝硬化的风险。Vonafexor （VON）是第二代合成非甾体、非胆汁酸法内甾体X受体激动剂，已被证明可预防肝纤维化并靶向HBV cccDNA库。然而，坚持每日口服治疗是成功治疗慢性感染的一个既定障碍。为了克服这一障碍，VON被转化为长效（LA）前药纳米混悬液。LA前药制剂可抑制LX2肝星状细胞α - sma、tgf - β和Col1A1基因的表达。在四氯化碳诱导的慢性肝损伤模型中，该制剂耐受性良好，可预防肝和肺损伤。有希望的临床前数据支持进一步开发LA VON前药作为肝和肺纤维化的潜在治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomolecules Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

3.60%

发文量

1640

审稿时长

18.28 days

期刊介绍： Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.