Jiangsu Key Laboratory of Draggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Br J Pharmacol. 2024 Aug;181(16):2923-2946. doi: 10.1111/bph.16378. Epub 2024 Apr 28.
Because of the absence of effective therapies for metabolic dysfunction-associated steatohepatitis (MASH), there is a rising interest in fibroblast growth factor 21 (FGF21) analogues due to their potential anti-fibrotic activities in MASH treatment. PsTag-FGF21, a long-acting FGF21 analogue, has demonstrated promising therapeutic effects in several MASH mouse models. However, its efficacy and mechanism against MASH-related fibrosis remain less well defined, compared with the specific mechanisms through which FGF21 improves glucose and lipid metabolism.
The effectiveness of PsTag-FGF21 was evaluated in two MASH-fibrosis models. Co-culture systems involving macrophages and hepatic stellate cells (HSCs) were employed for further assessment. Hepatic macrophages were selectively depleted by administering liposome-encapsulated clodronate via tail vein injections. RNA sequencing and cytokine profiling were conducted to identify key factors involved in macrophage-HSC crosstalk.
We first demonstrated the significant attenuation of hepatic fibrosis by PsTag-FGF21 in two MASH-fibrosis models. Furthermore, we highlighted the crucial role of macrophage phenotypic switch in PsTag-FGF21-induced HSC deactivation. FGF21 was demonstrated to regulate macrophages in a PsTag-FGF21-like manner. NR4A1, a nuclear factor which is notably down-regulated in human livers with MASH, was identified as a mediator responsible for PsTag-FGF21-induced phenotypic switch. Transcriptional control over insulin-like growth factor 1, a crucial factor in macrophage-HSC crosstalk, was exerted by the intrinsically disordered region domain of NR4A1.
Our results have elucidated the previously unclear mechanisms through which PsTag-FGF21 treats MASH-related fibrosis and identified NR4A1 as a potential therapeutic target for fibrosis.
由于代谢相关脂肪性肝炎（MASH）缺乏有效的治疗方法，因此人们对成纤维细胞生长因子 21（FGF21）类似物越来越感兴趣，因为它们在 MASH 治疗中具有潜在的抗纤维化活性。PsTag-FGF21 是一种长效 FGF21 类似物，在几种 MASH 小鼠模型中显示出有希望的治疗效果。然而，与 FGF21 改善葡萄糖和脂质代谢的具体机制相比，其针对 MASH 相关纤维化的疗效和机制仍不明确。
在两种 MASH 纤维化模型中评估了 PsTag-FGF21 的有效性。使用涉及巨噬细胞和肝星状细胞（HSC）的共培养系统进行进一步评估。通过尾静脉注射包裹在脂质体中的氯膦酸盐选择性耗尽肝巨噬细胞。进行 RNA 测序和细胞因子谱分析以鉴定参与巨噬细胞-HSC 串扰的关键因素。
我们首先证明了 PsTag-FGF21 在两种 MASH 纤维化模型中显著减轻了肝纤维化。此外，我们强调了巨噬细胞表型转换在 PsTag-FGF21 诱导的 HSC 失活中的关键作用。FGF21 以类似于 PsTag-FGF21 的方式调节巨噬细胞。NR4A1 是一种在具有 MASH 的人类肝脏中明显下调的核因子，被鉴定为负责 PsTag-FGF21 诱导的表型转换的介质。NR4A1 的无规卷曲结构域对巨噬细胞-HSC 串扰中的关键因子胰岛素样生长因子 1 进行转录控制。
我们的结果阐明了以前不清楚的 PsTag-FGF21 治疗 MASH 相关纤维化的机制，并确定了 NR4A1 作为纤维化的潜在治疗靶点。
