Proteomic signature of MASLD heterogeneity reveals sex-driven endotypes and predicts all-cause mortality.

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) represents a systemic metabolic hub where overlapping cardiometabolic risk factors frequently obscure individualized prognostic trajectories. While MASLD is a known driver of systemic risk, the molecular endotypes that dictate clinical outcomes across the disease spectrum remain poorly defined. We utilized a population-wide proteomic framework to resolve the MASLD cardiometabolic spectrum, identifying the sex-driven molecular endotypes that bridge hepatic dysfunction with systemic mortality. MethodsWe applied latent class analysis (LCA) to 48,806 UK Biobank participants with MRI-PDFF data to define phenotypic clusters across a >15-year follow-up. Large-scale proteomic profiling was integrated to characterize the molecular architecture of these identified clusters. This led to the derivation of a four-protein score (PS4), which was robustly validated for all-cause mortality prediction in an expanded cohort (n=115,979) and an external replication cohort. Causal mediation analysis was employed to quantify the biological contribution of these circulating and hepatic-expressed proteins to the observed clinical outcomes. ResultsThe LCA resolved the MASLD spectrum into clinically distinct endotypes, revealing a pronounced sexual dimorphism where high-risk subgroups displayed accelerated cardiometabolic decline. The PS4 score--comprising proteins linked to hepatic lipid metabolism (FABP1), one-carbon metabolism (FTCD), and immune-vascular integrity (ADGRG1, GAST)--demonstrated superior performance in predicting systemic mortality compared to established clinical scores. Mediation analysis revealed that these proteins account for a substantial causal fraction (10-24%) of the association between MASLD endotypes and mortality, independent of traditional risk factors such as age, sex, hypertension and type 2 diabetes. ConclusionsOur findings demonstrate that MASLD-driven proteomic shifts provide a mechanistic link between hepatic metabolic dysfunction and systemic survival. By resolving the MASLD cardiometabolic spectrum, we identified high-risk endotypes that are not captured by traditional liver-centric scores. The PS4 signature represents a biologically grounded framework for deciphering the systemic consequences of MASLD and its associated cardiometabolic complications, offering a scalable tool to identify individuals at the highest risk for adverse outcomes and facilitating a precision medicine approach to cardiometabolic disease.