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Liver fibrosis and MAFLD: the exploration of multi-drug combination therapy strategies.

ABSTRACT: In recent years, the prevalence of metabolic-associated fatty liver disease (MAFLD) has reached pandemic proportions as a leading cause of liver fibrosis worldwide. However, the stage of liver fibrosis is associated with an increased risk of severe liver-related and cardiovascular events and is the strongest predictor of mortality in MAFLD patients. More and more people believe that MAFLD is a multifactorial disease with multiple pathways are involved in promoting the progression of liver fibrosis. Numerous drug targets and drugs have been explored for various anti-fibrosis pathways. The treatment of single medicines is brutal to obtain satisfactory results, so the strategies of multi-drug combination therapies have attracted increasing attention. In this review, we discuss the mechanism of MAFLD-related liver fibrosis and its regression, summarize the current intervention and treatment methods for this disease, and focus on the analysis of drug combination strategies for MAFLD and its subsequent liver fibrosis in recent years to explore safer and more effective multi-drug combination therapy strategies.

SUBMITTER: Dong Q

PROVIDER: S-EPMC10157161 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Liver fibrosis and MAFLD: the exploration of multi-drug combination therapy strategies.

Dong Qingfu Q Bao Haolin H Wang Jiangang J Shi Wujiang W Zou Xinlei X Sheng Jialin J Gao Jianjun J Guan Canghai C Xia Haoming H Li Jinglin J Kang Pengcheng P Xu Yi Y Cui Yunfu Y Zhong Xiangyu X

Frontiers in medicine 20230420

In recent years, the prevalence of metabolic-associated fatty liver disease (MAFLD) has reached pandemic proportions as a leading cause of liver fibrosis worldwide. However, the stage of liver fibrosis is associated with an increased risk of severe liver-related and cardiovascular events and is the strongest predictor of mortality in MAFLD patients. More and more people believe that MAFLD is a multifactorial disease with multiple pathways are involved in promoting the progression of liver fibros ...[more]

PMID: 37153080

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Project description:Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFβ fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, β-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFβ cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.

Dataset Information

Liver fibrosis and MAFLD: the exploration of multi-drug combination therapy strategies.

Publications

Liver fibrosis and MAFLD: the exploration of multi-drug combination therapy strategies.

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