An Integrated Systematic Review and Meta‐Analysis From the Bloodstream to Identify Potential Biomarkers for ALD, MASLD, and HCC Without a Viral Background

Chronic non-viral liver diseases (CNVLD), including alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), have increased in prevalence, surpassing viral hepatitis as the main cause of hepatocellular carcinoma (HCC) in the last decade; thus, the identification of bloodstream biomarkers is essential for early diagnosis, risk stratification, and monitoring progression. This study aimed to systematically integrate and compare proteomic evidence from blood-based studies to identify differentially expressed proteins (DEPs) associated with ALD, MASLD, and HCC of non-viral etiology, to prioritize them as candidates for shared biomarkers and diagnostics for each disease. A systematic review was conducted, followed by a qualitative meta-analysis to identify DEPs bloodstream biomarkers. Biomarkers were compared across diseases to detect overlaps. Functional enrichment, network, and topological analyses were used to evaluate their biological relevance. We identified 16 diagnostic biomarkers for ALD, 53 for MASLD, and 8 for HCC. Four biomarkers were shared among ALD and MASLD, two among ALD and HCC, and two among MASLD and HCC. Functional analyses indicated platelet dysfunction and coagulation pathway alterations in ALD; lipid metabolism dysregulation in MASLD; and a combination of these processes in HCC patients. Network analysis highlighted key biomarkers with potential diagnostic and prognostic applications. The identified biomarkers reflect both shared and disease-specific molecular mechanisms in the progression of CNVLD toward HCC. Their consistent presence across independent studies supports their potential integration into diagnostic and prognostic panels, particularly in the context of the rising prevalence of ALD and MASLD worldwide.