From Multiomics Discovery to Clinical Validation: Identification of Novel Noninvasive Biomarkers for Liver Fibrosis.

Early diagnosis of liver fibrosis is vital for preventing cirrhosis. Through integrated multiomics and single-cell sequencing, we identified Thrombospondin 2 (THBS2), Growth Differentiation Factor 15 (GDF15), and Neurofascin (NFASC) as prioritized biomarkers, exhibiting prominent expression in fibroblasts and hepatocytes. In vivo studies confirmed their significant upregulation and distinct colocalization in fibrotic livers. Clinical validation showed significant biomarker elevation correlating with fibrosis severity (q < 0.001). THBS2 and GDF15 demonstrated superior diagnostic accuracy (AUCs > 0.94) over FIB-4, while NFASC effectively discriminated early-stage (F0-2) from advanced (F3-4) fibrosis (AUC = 0.877). To optimize precision, we developed a multivariable model integrating these biomarkers with clinical variables (Age, Sex, ALT, AST, PLT). This model achieved an excellent AUC of 0.925 (95% CI: 0.941-0.998), significantly enhancing risk stratification over the BiomarkerOnly model (NRI = 1.198, p < 0.001). In conclusion, through a translational study combining multiomics and experimental validation, we characterized THBS2, GDF15, and NFASC as novel biomarkers for liver fibrosis, offering a promising strategy for noninvasive stratification and monitoring of fibrosis.