Ruigong Zhu

Disturbance of macrophage-associated lipid metabolism plays a key role in atherosclerosis. Crosstalk between autophagy deficiency and inflammation response in foam cells (FCs) through epigenetic regulation is still poorly understood. Here, we demonstrate that in macrophages, oxidized low-density lipoprotein (ox-LDL) leads to abnormal crosstalk between autophagy and inflammation, thereby causing aberrant lipid metabolism mediated through a dysfunctional transcription factor EB (TFEB)–P300–bromodomain-containing protein 4 (BRD4) axis. ox-LDL led to macrophage autophagy deficiency along with TFEB cytoplasmic accumulation and increased reactive oxygen species generation. This activated P300 promoted BRD4 binding on the promoter regions of inflammatory genes, consequently contributing to inflammation with atherogenesis. Particularly, ox-LDL activated BRD4-dependent super-enhancer associated with liquid–liquid phase separation (LLPS) on the regulatory regions of inflammatory genes. Curcumin (Cur) prominently restored FCs autophagy by promoting TFEB nuclear translocation, optimizing lipid catabolism, and reducing inflammation. The consequences of P300 and BRD4 on super-enhancer formation and inflammatory response in FCs could be prevented by Cur. Furthermore, the anti-atherogenesis effect of Cur was inhibited by macrophage-specific Brd4 overexpression or Tfeb knock-out in Apoe knock-out mice via bone marrow transplantation. The findings identify a novel TFEB-P300-BRD4 axis and establish a new epigenetic paradigm by which Cur regulates autophagy, inhibits inflammation, and decreases lipid content.

) mouse peritoneal macrophages, and human peripheral blood mononuclear cells (PBMCs). We found Lipopolysaccharide (LPS) could induce the formation of senescent macrophages, which was typified by the morphological changes, senescence-associated secretory phenotype (SASP) secretory, and persistent DNA damage response. Mechanistically, bromodomain-containing protein 4 (BRD4), a chromosomal binding protein related to gene expression, was found to play a key role in the pathological process, which could offer new therapeutic perspectives. Inhibition of BRD4 by siBRD4 or inhibitors such as JQ-1 or I-BET762 prevented the aging of macrophages and lipid accumulation in the LPS-induced senescent macrophages by decreasing expression of SASP in autocrine and paracrine senescence. These findings have significant implications for the understanding of the pathobiology of age-associated diseases and may guide future studies on targeted clinical drug therapy.

Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)–PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and NF-κB, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING–PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the promoters of proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondria DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING–PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction.

Cellular senescence is closely associated with age-related diseases. Ovarian aging, a special type of organ senescence, is the pathophysiological foundation of the diseases of the reproductive system. It is characterized by the loss of integrity of the surface epithelium and a gradual decrease in the number of human ovarian surface epithelial cells (HOSEpiCs). To contribute to the research on delaying ovarian aging, we aimed to investigate the novel epigenetic mechanism of melatonin in protecting HOSEpiCs. We discovered that melatonin has antagonistic effects against the oncogene-induced senescence (OIS) of HOSEpiCs. Mechanistically, the oncogene Ras decreased the expression of YTHDF2, which is the reader of RNA-m6A, by stimulating the generation of reactive oxygen species (ROS). Moreover, we found that the suppression of YTHDF2 increased the expression of MAP2K4 and MAP4K4 by enhancing the stability of the transcription of their mRNAs, thereby upregulating the expression of the senescence-associated secretory phenotype (SASP) through the activation of the MAP2K4 and MAP4K4-dependent nuclear factor-κB (NF-κB) signaling pathways. We further determined that melatonin has antagonistic effects against the OIS of HOSEpiCs by inhibiting the ROS-YTHDF2-MAPK-NF-κB pathway. These findings provide key insights into the potential avenues for preventing and treating ovarian aging.