Homocysteine-Methionine (HM) cycle produces a universal methyl group donor S-adenosylmethionine (SAM), a competitive methylation inhibitor S-adenosylhomocysteine (SAH), and an intermediate amino acid product homocysteine (Hcy). Elevated plasma levels of Hcy is termed as hyperhomocycteinemia (HHcy) which is an established risk factor for cardiovascular disease (CVD) and neural degenerative disease. We were the first to describe methylation inhibition as a mediating biochemical mechanism for endothelial injury and inflammatory monocyte differentiation in HHcy-related CVD and diabetes. We proposed metabolism-associated danger signal (MADS) recognition as a novel mechanism for metabolic risk factor-induced inflammatory responses, independent from pattern recognition receptor (PRR)-mediated pathogen-associated molecular pattern (PAMP)/danger-associated molecular pattern (DAMP) recognition. In this study, we examined the relationship of HM cycle gene expression with methylation regulation in human disease. We selected 115 genes in the extended HM cycle, including 31 metabolic enzymes and 84 methyltransferases (MT), examined their mRNA levels in 35 human disease conditions using a set of public databases. We discovered that: 1) HM cycle senses metabolic risk factor and controls SAM/SAH-dependent methylation. 2) Most of metabolic enzymes in HM cycle (8/11) are located in cytosol, while most of the SAM-dependent MTs (61/84) are located in the nucleus, and Hcy metabolism is absent in the nucleus. 3) 11 up-regulated, 3 down-regulated and 24 differentially regulated SAM/SAH-responsive signal pathways are involved in 7 human disease categories. 4) 8 SAM/SAH-responsive H3/H4 hypomethylation sites are identified in 8 disease conditions. We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent MADS recognition and modulates SAM/SAH-dependent methylation in human disease. We propose that HM metabolism takes place in cytosol and that nuclear methylation equilibration requires nuclear-cytosol transfer of SAM, SAH and Hcy. CD40 is a cell surface molecule which is expressed on antigen presenting cells such as monocyte, macrophage, dendritic cells and neutrophils. The costimulatory pair, CD40 and CD40L, enhances T cell activation and induce chronic inflammatory disease. Also, DNA hypomethylation on CD40 promotor induces inflammatory monocyte differentiation in chronic kidney disease. In order to figure out if CD40 is a prototypic HM cycle regulated master gene, RNA-seq analysis were performed for CD40+ and CD40- monocytes from mouse peripheral blood and 1,093 differentially expressed genes (DEGs) were selected from those two groups. All the DEGs modulate as much as 15 functional gene groups such as cytokines, enzymes and transcriptional factors. Furthermore, CD40+ monocytes activated trained immunity pathways especially in Acetyl-CoA generation and mevalonate pathway. In HM cycle, CD40 is a prototypic HM cycle regulated master gene to induce the most of the Hcy metabolic enzymes as well as MT, which can further modulate the methylation-regulated pathological signaling. / Biomedical Sciences