Fuhao Liu

Macrophage activation is a hallmark of atherosclerosis, accompanied by a switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and histone modifications in macrophages is worthy of further investigation. Here, we find that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated histone lactylation is closely related to atherosclerosis. Histone H3 lysine 18 lactylation dependent on MCT4 deficiency activated the transcription of anti-inflammatory genes and tricarboxylic acid cycle genes, resulting in the initiation of local repair and homeostasis. Strikingly, histone lactylation is characteristically involved in the stage-specific local repair process during M1 to M2 transformation, whereas histone methylation and acetylation are not. Gene manipulation and protein hydrolysis-targeted chimerism technology are used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and histone modifications, plays a key role in training macrophages to become repair and homeostasis phenotypes.

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo, as well as in atherosclerotic patients’ arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1, thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on ApoeKOAsf1aECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis.

In this study, modified coal fly ash (NMFA) was prepared by sodium hydroxide (NaOH) with low-temperature hydrothermal method. The differences of the ash to alkali mass ratio (5:3, 5:4, 5:5, 5:6), calcination temperature (100 ℃, 200 ℃, 300 ℃), and calcination time (1 h, 3 h, 5 h) were investigated. The adsorption experiments obtained the optimal result with the ash to base ratio of 5:5, calcination temperature of 200 ℃, and calcination time of 3 h, adsorbing 90.27 mg/g of Cd2+. The characterization results (SEM-EDS, FTIR, XRD, and XPS) also confirmed the effective adsorption of Cd2+ by NMFA. The functional groups of Si-O, Al-O, and Fe-O played an important role in Cd2+ removal. Meanwhile, the influences of dosage, different pH, and co-existing cations were also investigated. Quasi-secondary adsorption kinetics and Langmuir isotherm model were also referred to the Cd2+ adsorption by NMFA. Therefore, the good adsorption of NMFA-3 on Cd2+ provided new ideas for the safe utilization of fly ash and heavy metal purification in wastewater.