Macrophage HERC6 Promotes NAFLD: Integrated Analyses of Mendelian Randomization and Single-Cell Transcriptome

Aims and Objectives: This study aimed to explore the relationship between HERC6- associated immune response and Non-Alcoholic Fatty Liver Disease (NAFLD) and to screen drug candidates for novel treatments. Materials and Methods: Mendelian Randomization (MR) was performed to test the relationship between a genetically predicted increase in HERC6 expression and the development of NAFLD. A single-cell RNA-seq profile of liver tissue with histological characteristics (GSE168933) was obtained. The immune cell type with the highest HERC6 score was identified, and the HERC6 scores across hepatic steatosis, ballooning, and lobular inflammation were compared. Bulk RNA data of liver samples from obese patients who underwent diet restriction or bariatric surgery (GSE83452) was deconvoluted, and the proportions of distinct HERC6-high immune cell subpopulations were estimated. The baseline and follow-up differences were compared to evaluate the effectiveness of different therapies. Finally, a single-cell drug susceptibility assessment was performed to screen drug candidates targeting HERC6-associated immune cells. Results: MR results showed that an increase in HERC6 expression was associated with an increase in low-density lipoprotein cholesterol (LDL-C) level and the development of NAFLD. The HERC6 score on monocyte-derived macrophage was the highest and positively correlated with hepatic steatosis, ballooning, and lobular inflammation. The HERC6-high macrophage fraction significantly decreased after bariatric surgery but not diet therapy. Triptolide was identified as a potential drug for NAFLD targeting HERC6-high macrophages. Conclusion: The results highlighted the role of hepatic macrophage HERC6 in NAFLD