| Title: | A role of FURIN in promoting TGF-β signaling activation in MAFLD: Evidence from UK Biobank proteomic cohort |
| Journal: | International Journal of Biological Macromolecules |
| Published: | 30 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41621513/ |
| DOI: | https://doi.org/10.1016/j.ijbiomac.2026.150634 |
Publication 18413
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Abstract
Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a highly prevalent condition, yet its molecular mechanisms remain incompletely understood. We explored circulating protein signatures and their causal relationships with MAFLD using large-scale proteomic and genomic data from the UK Biobank. Baseline plasma levels of 2923 circulating proteins were quantified in 49,206 participants (744 MAFLD outcomes). Protein-MAFLD associations were evaluated using multivariable Cox regression, followed by cis-Mendelian randomization (cis-MR) to infer causal effects based on protein quantitative trait loci. Among 215 proteins associated with MAFLD risk, four proteins (FURIN, LILRB4, NFASC, and PRAP1) showed causal evidence by cis-MR. FURIN, a proprotein convertase that activates transforming growth factor-β (TGF-β), emerged as the strongest causal effector. Downstream TGF-β signaling molecules (TGFB1, TGFBR2, SMAD1, and SMAD5) were significantly elevated in MAFLD cases, supporting activation of the FURIN/TGF-β axis. Additionally, 30 TNF-α-related proteins, including TNF, TNFRSF1A, TNFRSF1B, JUN, FOS, MAPK9, and MAPK13, were significantly upregulated in MAFLD, suggesting upstream regulation of FURIN by inflammatory TNF-α signaling. Our integrative cohort and genetic analyses reveal FURIN as a causal mediator in MAFLD pathogenesis through activation of TGF-β signaling, potentially modulated by inflammatory TNF-α signaling. These findings highlight the TNF-α/FURIN/TGF-β cascade as a potential molecular target for early prediction and therapeutic intervention in MAFLD.</p>
12 Keywords
- Biological Specimen Banks
- Cohort Studies
- Female
- Furin
- Humans
- Male
- Middle Aged
- Proteomics
- Signal Transduction
- Transforming Growth Factor beta
- UK Biobank
- United Kingdom
12 Authors
- Hao Wang
- Xingang Li
- Xiaoqian Xu
- Shun Li
- Weiming Li
- Lichen Shi
- Cheng Huang
- Yameng Sun
- Hong You
- Jidong Jia
- You-Wen He
- Yuanyuan Kong
1 Application
| Application ID | Title |
|---|---|
| 129053 | Screening biomarkers for NAFLD/NASH using proteomics and Mendelian Randomization |
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