Identification and in vitro validation of causative proteins in metabolic dysfunction-associated fatty liver disease: A study based on proteome-wide Mendelian randomization

Jianyi Chen; Wentao Huang; Yang Li; Zewei Zhuo; Qinming Li; Yu Long; Weihong Sha; Hao Chen

doi:10.12449/JCH260911

Volume 42 Issue 9

Sep. 2026

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Article Navigation > Journal of Clinical Hepatology > 2026 > 42(9): 2067-2074

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Identification and in vitro validation of causative proteins in metabolic dysfunction-associated fatty liver disease: A study based on proteome-wide Mendelian randomization

DOI: 10.12449/JCH260911

Jianyi Chen^{1, 2},
Wentao Huang²,
Yang Li²,
Zewei Zhuo^{1, 2},
Qinming Li²,
Yu Long^{1, 2},
Weihong Sha^{1, 2
,
,
,},
Hao Chen^{1, 2
,
,
,}

1.
School of Medicine，South China University of Technology，Guangzhou 510006，China
2.
Department of Gastroenterology，Guangdong Provincial People’s Hospital，Guangzhou 510080，China

Research funding:

Natural Science Foundation of Guangdong Province (2022A1515012081)

More Information

Corresponding author: Sha Weihong， shaweihong@gdph.org.cn （ORCID： 0000-0001-7610-3813）; Chen Hao， chenhao@gdph.org.cn （ORCID： 0000-0003-4339-3441）
Received Date: 2026-03-04
Accepted Date: 2026-04-03
Published Date: 2026-09-25

Abstract

Abstract

Objective To identify protein biomarkers and potential therapeutic targets associated with metabolic dysfunction-associated fatty liver disease （MAFLD） through an integrative multi-omics analysis. Methods Large-scale plasma protein quantitative trait locus data were integrated with MAFLD genome-wide association study data， and a proteome-wide Mendelian randomization analysis was performed. Summary data-based Mendelian Randomization （SMR）/heterogeneity in dependent instruments （HEIDI） test and colocalization analysis were used to assess significant proteins. The independent samples t-test was used for comparison of continuous data with homogeneity of variance between two groups， and the Welch-corrected t-test was used for comparison of continuous data with heterogeneity of variance. The transcriptomic validation results were compared with the Mendelian randomization results to evaluate the changing trends of gene expression， and boxplots were used to display the expression distribution of candidate genes between groups. Results Among 7 130 proteins analyzed， 40 showed a causal relationship with MAFLD， among which 26 increased the risk of MAFLD and 14 exerted a protective effect against MAFLD （FDR<0.05）. Nine proteins were supported by SMR/HEIDI （P_SMR<0.05， P_HEIDI>0.05）， and 14 showed a strong colocalization signal （PPH₄>0.9）. The transcriptomic analysis identified 5 differentially expressed proteins （all P<0.05）， i.e.， adenosine diphosphate-ribosylation factor-like GTPase 2， insulin-like growth factor binding protein 2， casein kinase 1 delta （CSNK1D）， leucine-rich repeat neuronal 1， and moesin （MSN）. In vitro validation showed upregulated expression levels of MSN （1.612±0.346 vs 0.569±0.077， P<0.05）， 14-3-3 protein theta （YWHAQ）（1.267±0.126 vs 0.313±0.029， P<0.05）， and CSNK1D （0.871±0.025 vs 0.431±0.080， P<0.05） and a downregulated expression level of histone deacetylase 8 （0.637±0.059 vs 1.097±0.260， P<0.05） in the MAFLD cell model. Functional annotation showed that CSNK1D participated in circadian and metabolic regulation， YWHAQ modulated the Hippo pathway and lipid signal transduction， and MSN was associated with cytoskeletal remodeling and fibrogenic responses. Conclusion The integrative proteogenomic analysis in this study shows that CSNK1D， YWHAQ， and MSN may be key mediators in the pathogenesis of MAFLD. These proteins have the potential to serve as novel biomarkers and therapeutic targets， providing new directions for research on disease mechanisms and the development of intervention strategies.
- Metabolic Dysfunction-Associated Fatty Liver Disease,
- Proteome,
- Mendelian Randomization Analysis,
- Therapeutics

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Identification and in vitro validation of causative proteins in metabolic dysfunction-associated fatty liver disease: A study based on proteome-wide Mendelian randomization

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Identification and in vitro validation of causative proteins in metabolic dysfunction-associated fatty liver disease: A study based on proteome-wide Mendelian randomization

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