Serum SOS1 as a prognostic biomarker and therapeutic target for progressive liver disease

Given the lack of a reliable prognostic biomarker for the serial progression of chronic liver disease, we investigated SOS1 linked to stellate cells-driven liver disease progression. A cohort of 556 participants stratified into F0-F1, F2-F3, F4, and HCC, was followed for up to 36 months, measuring serial SOS1 and comparators, modeling outcome discrimination and trajectories, and validating biologic relevance via SOS1 inhibition in stellate cells and a chronic-injury mouse model. SOS1 increased stepwise with disease stage and correlated with APRI and FIB-4 (p < 0.001). Higher baseline SOS1 predicted mortality (HR 1.78, 95% CI 1.32-2.41), outperforming AFP and MELD, with AUC(t) = 0.82 at 36 months. Steeper SOS1 trajectories conferred higher death risk. In TCGA-LIHC, SOS1 remained independently prognostic. Pharmacological inhibition of SOS1 reduced fibrogenic gene expression and attenuated fibrosis in vivo and in vitro. SOS1 showed a stage-responsive, quantitatively validated biomarker linking clinical risk stratification with fibrogenic biology in liver disease.