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Metab.-Clin. Exp., Available online 8 June 2025, 156323 | https://doi.org/10.1016/j.metabol.2025.156323
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
Su Ho Jo a,b, Eun Soo Lee a, So Bin Lee a,b, Kyung Bong Ha c, Choon Hee Chung a,b
aDepartment of Internal Medicine and Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
bDepartment of Global Medical Science and Graduate program for the next generation global leaders in biomedical science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
cDepartment of Clinical research team, Vaccine center for assisting safety and technology, Hwasun 58141, Republic of Korea
Corresponding author : Choon Hee Chung
aDepartment of Internal Medicine and Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
bDepartment of Global Medical Science and Graduate program for the next generation global leaders in biomedical science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
cDepartment of Clinical research team, Vaccine center for assisting safety and technology, Hwasun 58141, Republic of Korea
Corresponding author : Choon Hee Chung
Abstract
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.
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 Csingle bondC 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.
논문정보
- Research article
- 2025년 06월 (BRIC 등록일 2025-06-11)
- 국내 연구진
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