Wenjing Zhang,1,* Shuai Ji,2,* Ren Chen,1 Nabao Chen,1 Xiaoshan Zhao,3 Dong Han,4 Ruiqing Dong,5 Zhaoting Hu1 

1Department of Health Management Center, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Traditional Chinese Medicine, Southern Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Quality Control and Evaluation, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 5Guangzhou College of Commerce, Guangzhou, Guangdong, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Ruiqing Dong, Email 20230061@gcc.edu.cn Zhaoting Hu, Email huzhaoting123@smu.edu.cn

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.

Keywords: The monocyte-to-high-density lipoprotein cholesterol ratio, metabolic dysfunction-associated fatty liver disease, trajectory anaylsis, Mendelian randomization