Plasma IGFBP7 improves risk reclassification for liver-related outcomes: Insights from proteo-transcriptomic profiling

Background & Aims: Advanced liver fibrosis is a pivotal predictor of liver-related outcomes (LROs), yet existing non-invasive tests offer limited prognostic accuracy. We aimed to identify novel plasma protein biomarkers that enhance long-term risk stratification for LROs. Methods: Proteomic analyses were first conducted in 191 patients with metabolic dysfunction-associated steatotic liver disease (MASLD), including 79 with advanced fibrosis and 112 with mild fibrosis, to identify differential plasma proteins. These proteomic findings were then integrated with liver transcriptional profiling from 206 patients with MASLD, comprising 68 with advanced fibrosis and 138 with mild fibrosis, to determine candidate biomarkers. The prognostic utility of these biomarkers was validated in 42,979 participants from the UK Biobank with a median follow-up of 13 years. Discriminatory performance and cumulative incidence were assessed using competing-risk methodologies. Results: , identified a high-risk subgroup with a 20% 15-year incidence of cirrhosis. Subgroup analyses showed consistent prognostic value across MASLD, metabolic dysfunction-associated alcohol-related liver disease, and alcohol-related liver disease, with particularly strong performance in MASLD (15-year AUCs >0.85). Conclusions: Plasma IGFBP7 is a robust and independent predictor of liver-related outcomes and significantly enhances risk stratification beyond conventional clinical tools. Impact and implications: those suitable for reduced monitoring, potentially optimizing care pathways in resource-limited settings. Moreover, IGFBP7 demonstrated consistent applicability across all categories of steatotic liver disease defined by the current Delphi consensus framework, underscoring its broad clinical utility.