A role of FURIN in promoting TGF-β signaling activation in MAFLD: Evidence from UK Biobank proteomic cohort
Author Identifier (ORCID)
Xingang Li: https://orcid.org/0000-0003-0252-154X
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.
Document Type
Journal Article
Date of Publication
2-1-2026
Volume
347
Publication Title
International Journal of Biological Macromolecules
Publisher
Elsevier
School
School of Medical and Health Sciences
Funders
National Key Research and Development Program, China (2023YFC2306902, 2023YFC2306900) / High-level Public Health Technical Talents of the Beijing Municipal Health Commission, China (XUEKEGUGAN-010-018) / Beijing Natural Science Foundation (L252176) / Beijing Municipal Administration of Hospitals Incubating Program (PX2024003)
Copyright
subscription content
Comments
Wang, H., Li, X., Xu, X., Li, S., Li, W., Shi, L., Huang, C., Sun, Y., You, H., Jia, J., He, Y., & Kong, Y. (2026). A role of FURIN in promoting TGF-β signaling activation in MAFLD: Evidence from UK Biobank proteomic cohort. International Journal of Biological Macromolecules, 347, 150634. https://doi.org/10.1016/j.ijbiomac.2026.150634