Emerging Biomarkers in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Current Evidence, Clinical Utility, and Future Perspectives.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and represents the hepatic manifestation of metabolic syndrome. The disease spectrum ranges from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Liver biopsy remains the histological reference standard for assessing steatohepatitis and microscopic disease activity and is valuable in selected cases; however, contemporary MASLD management increasingly relies on validated non-invasive tests for fibrosis risk stratification, with biopsy generally reserved for diagnostic uncertainty, discordant non-invasive findings, or situations in which histological information would alter management. This review aims to summarize the biochemical basis, pathophysiological mechanisms, current evidence, clinical utility, and limitations of emerging non-invasive biomarkers for the diagnosis, staging, and longitudinal monitoring of MASLD. A comprehensive narrative review of recent advances in molecular biology, metabolomics, proteomics, and inflammatory pathway research was conducted, synthesizing evidence on promising circulating biomarkers and their role in reflecting hepatic steatosis, lipotoxicity, apoptosis, inflammation, and fibrogenesis. This narrative review was conducted through a structured literature search of PubMed/MEDLINE, Scopus, and Google Scholar. Search terms included combinations of 'metabolic dysfunction-associated steatotic liver disease,' 'MASLD,' 'MASH,' 'non-invasive biomarkers,' 'cytokeratin-18,' 'FGF-21,' 'adipokines,' 'cytokines,' 'extracellular vesicles,' 'microRNAs,' 'metabolomics,' 'gut microbiota,' 'fibrosis biomarkers,' and 'non-invasive liver tests.' Priority was given to human studies, systematic reviews, meta-analyses, multicenter validation studies, and major professional-society guidelines relevant to the diagnosis, fibrosis risk stratification, prognosis, and treatment-response monitoring of MASLD. Reference lists of relevant articles were additionally reviewed to identify pertinent studies. As this was a narrative rather than a systematic review, no formal meta-analysis or standardized risk-of-bias assessment was performed. Recent research has identified several promising biomarkers, including cytokeratin-18 fragments, fibroblast growth factor-21 (FGF-21), adipokines, inflammatory cytokines, extracellular vesicles, circulating microRNAs, metabolomic signatures, and gut microbiota-derived metabolites. These biomarkers have demonstrated potential not only for diagnosing MASLD and distinguishing steatohepatitis from simple steatosis but also for predicting disease progression and monitoring therapeutic responses. However, no single biomarker currently meets all criteria to universally replace liver biopsy. Integrated multi-marker panels, enhanced by genetic data and artificial intelligence-driven algorithms, represent the most pragmatic strategy moving forward, with the aspirational goal of achieving a non-invasive, blood-based "virtual liver biopsy" in routine clinical practice.