The Impact of the Trajectory of the Monocyte-to-High-Density Lipoprotein Cholesterol Ratio on the Incidence of Metabolic Dysfunction-Associated Fatty Liver Disease: Random Forest Anaylsis, Trajectory Anaylsis, and Mendelian Randomization Study.

Background and Aims: The monocyte-to-high-density lipoprotein cholesterol ratio (MHR) has emerged as a novel biomarker integrating inflammation and lipid metabolism, but its longitudinal association with metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. This study aimed to investigate the impact of MHR trajectories on MAFLD risk using multidisciplinary approaches. Methods: We conducted a comprehensive anaylsis combining: (1) machine learning-based random forest modeling to evaluate feature importance; (2) prospective cohort anaylsis with repeated MHR measurements to identify trajectory patterns; and (3) Mendelian randomization (MR) to infer causality. Results: Three distinct MHR trajectories were identified in the cohort. Compared to the low-stable group, both moderate-increasing (HR 1.17, 95% CI 1.04-1.32) and high-fluctuating (HR 1.24, 95% CI1.03-1.49) trajectories showed significantly higher MAFLD incidence. Random forest ranked MHR among top 5 predictors, and MR analyses supported a causal relationship. Conclusion: This multimodal study demonstrates that longitudinal MHR elevation precedes and predicts MAFLD development, implicating compounded inflammatory-lipid pathways. MHR trajectory anaylsis may enhance early risk stratification, particularly in metabolically compromised individuals.