Lung function, proteomic signatures, and risk of metabolic dysfunction-associated steatotic liver disease

• DOI: 10.21203/rs.3.rs-6381296/v1
• Publication Date: 2025-04-08T09:22:57Z
• Authors: Xianbo Wu; Rui Zhou; Qi Zhong; Xiu-Yi Wu; Haowen Chen; Yan-Fei Wei; Li Xiong; Xiao-Xiang Wu

Abstract The proteomic mechanisms bridging pulmonary function and metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive. Using proteomic data (2,920 proteins) from the UK Biobank (n = 47,055), we applied elastic net regression to identify plasma proteomic signatures related to three lung function measures (forced expiratory volume in one second [FEV1], forced vital capacity [FVC], and peak expiratory flow [PEF]) and explored their mediating role in lung function–MASLD associations. All pulmonary measures were inversely associated with incident MASLD. We identified 1345, 1317, and 108 circulating proteins as proteomic signatures for FVE1, FVC, and PEF, respectively. Proteomic signatures were associated with decreased risk of MASLD, with hazard ratios (HRs) and 95% confidence intervals (CIs) of 0.55 (0.47–0.65), 0.55 (0.47–0.65), and 0.54 (0.45–0.65), respectively. These proteomic signatures explained 37.4–94.8% of the protective associations between lung function and MASLD. Notably, the majority of signature proteins were enriched in pathways related to cytokine-cytokine receptor interactions and PI3K-Akt signaling. Consistent associations were observed between lung function, its proteomic signatures, and MRI-derived liver markers, including liver proton density fat fraction and corrected T1. Our findings suggested that improved lung function may protect against MASLD partly through modulation of circulating proteins linked to inflammatory and metabolic pathways.