CC趋化因子受体2抑制剂与转化生长因子-β I型受体激酶抑制剂联合治疗代谢功能障碍相关性脂肪性肝炎的协同作用

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental Pub Date : 2025-06-08 DOI:10.1016/j.metabol.2025.156323

Su Ho Jo , Eun Soo Lee , So Bin Lee , Kyung Bong Ha , Choon Hee Chung

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引用次数: 0

摘要

背景：代谢功能障碍相关脂肪性肝炎（MASH）是一种进行性肝脏疾病，其特征是与代谢异常相关，包括肥胖、高脂血症和2型糖尿病。以肝脂肪变性、炎症和纤维化为特征，MASH是一项重大的全球健康挑战，可用的药物选择有限。目前迫切需要针对参与MASH发病机制的关键分子通路的新型治疗策略。这两种药物联合治疗有望对MASH提供互补的预防和治疗效果。方法：本研究检测CC趋化因子受体2 （CCR2）抑制剂RS-102895联合TGF-β I型受体激酶抑制剂vactosertib治疗临床前MASH模型的疗效。通过组织学分析、血清生物标志物量化和基因表达谱来评估肝脏脂质积累、炎症、纤维化和代谢调节途径。结果：与单药治疗相比，联合治疗可显著改善组织学参数，减少肝脏炎症和纤维化标志物。值得注意的是，它导致脂质积累和炎症细胞因子的减少，同时恢复amp活化蛋白激酶（AMPK）的激活，AMPK是代谢调节剂的关键调节因子。该研究还发现rho相关蛋白激酶1 (ROCK1)/AMPK轴是MASH进展的中心介质。结论：双重抑制CCR2和TGF-β信号通路可能是治疗MASH的有效途径。通过解决脂质积累、炎症和纤维化，同时促进代谢平衡，该策略有望改善治疗这种复杂疾病的临床应用。

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Synergistic effects of C–C chemokine receptor 2 inhibitor and transforming growth factor-β type I receptor kinase inhibitor combination in metabolic dysfunction-associated steatohepatitis

Background

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive hepatic disorder characterized by its association with metabolic abnormalities, including obesity, hyperlipidemia, and type 2 diabetes mellitus. Characterized by hepatic steatosis, inflammation, and fibrosis, MASH presents a significant global health challenge, with limited pharmacological options available. There is a critical need for novel therapeutic strategies targeting key molecular pathways involved in MASH pathogenesis. Combination therapy with these two drugs is expected to provide complementary preventive and therapeutic effects against MASH.

Methods

This study examined the therapeutic efficacy of a C–C chemokine receptor 2 (CCR2) inhibitor (RS-102895) in combination with a TGF-β type I receptor kinase inhibitor (vactosertib) in preclinical MASH models. Histological analysis, serum biomarker quantification, and gene expression profiling were performed to assess hepatic lipid accumulation, inflammation, fibrosis, and metabolic regulatory pathways.

Results

Combination therapy significantly improved histological parameters and reduced liver inflammation and fibrosis markers compared with monotherapy. Notably, it led to reductions in lipid accumulation and inflammatory cytokines, alongside the restoration of AMP-activated protein kinase (AMPK) activation, a key regulator of metabolic regulator. The study also identified the Rho-associated protein kinase 1 (ROCK1)/AMPK axis as a central mediator of MASH progression.

Conclusions

These findings indicate that dual inhibition of CCR2 and TGF-β signaling pathways could serve as an effective therapeutic approach for MASH. By addressing lipid accumulation, inflammation, and fibrosis while promoting metabolic balance, this strategy holds promise for improved clinical applications in treating this complex disease.

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来源期刊

Metabolism: clinical and experimental 医学-内分泌学与代谢

CiteScore

18.90

自引率

3.10%

发文量

310

审稿时长

16 days

期刊介绍： Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism. Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential. The journal addresses a range of topics, including: - Energy Expenditure and Obesity - Metabolic Syndrome, Prediabetes, and Diabetes - Nutrition, Exercise, and the Environment - Genetics and Genomics, Proteomics, and Metabolomics - Carbohydrate, Lipid, and Protein Metabolism - Endocrinology and Hypertension - Mineral and Bone Metabolism - Cardiovascular Diseases and Malignancies - Inflammation in metabolism and immunometabolism