Associations of serum trace elements with liver fibrosis in adults: integration of metabolomics and network toxicology analysis

The association between multiple trace elements exposure and liver fibrosis, along with potential biological correlates, remains poorly understood. We conducted a longitudinal panel study among 205 adults with four repeated visits in Enshi, China. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were assessed using transient elastography, and serum trace elements and untargeted metabolomic profiles were measured. Linear mixed-effect models and mixture exposure models were applied to assess the individual and mixture associations, while a meet-in-the-middle (MITM) approach and network toxicology analysis were conducted to explore potential mediating metabolites and pathways. After adjusting for covariates, each 1-SD increase in serum zinc (Zn) was related to a 2.08% (95% CI: -3.40% to -0.74%, PFDR <0.05) decrease in LSM, whereas no significant associations were observed for CAP or elements mixtures. The exploratory MITM approach identified multiple overlapping metabolic pathways (e.g., pantothenate and CoA biosynthesis) and intermediate metabolites (e.g., citrate) linking Zn exposure with LSM. Furthermore, network toxicology analysis revealed that Zn-related liver fibrosis may predominantly involve apoptotic signaling, response to hypoxia, and lipid and atherosclerosis, with JUN, TNF, and IL6 as key hub genes. Collectively, higher serum Zn was inversely associated with liver fibrosis, and citrate- and CoA-centric pathways might represent key biological correlates.