Evaluating Hepatokines in the Progression of Non-alcoholic Fatty Acid Liver Disease by Decoding Liver-Derived Molecular Pathologies.

Non-alcoholic fatty liver disorder (NAFLD), also called metabolic dysfunction-associated steatotic liver disease (MASLD), is a leading cause of global liver disorders. Hepatokines are increasingly being used in the diagnosis of NAFLD. This study evaluated the association between the hepatokines and NAFLD progression and guided further therapeutic research. Data search was conducted across PubMed, Embase, Scopus, and Web of Science up to March 2025. Studies that assessed hepatokines in NAFLD were selected based on defined inclusion criteria. The Newcastle-Ottawa Scale (Version 2011), the Cochrane Risk of Bias 2 (RoB 2) tool, and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology were used to evaluate the RoB and the certainty of evidence. Pooled estimates were synthesized by using a random-effects meta-analysis model. Ten studies passed the eligibility criteria and involved a pooled sample size of 4,215 participants. Meta-analysis of six studies revealed that an increase in hepatokine levels was modestly correlated with NAFLD (odds ratio (OR) 1.11; 95% confidence interval (CI) 1.01-1.22; P = 0.037; I² = 84%). Individual biomarkers such as Fetuin-A, angiopoietin-like protein 8 (ANGPTL8), fibroblast growth factor 21 (FGF21), and retinol-binding protein 4 (RBP4) showed varying degrees of correlation. RoB was moderate across eight studies, low and high across one study each, and GRADE assessments displayed low to moderate quality of evidence. The research findings established a steady connection between NAFLD and variation in hepatokine levels. Fetuin-A and FGF21 showed promise as biomarkers against NAFLD diagnosis. However, uncertainty remained because of high variability and moderate levels of experimental bias. Further research needs to be conducted through standardized methods for assays in multicenter longitudinal studies to confirm hepatokine diagnostic and therapeutic effectiveness in treating patients with NAFLD.