Autophagy enhanced by curcumin ameliorates inflammation in atherogenesis via the TFEB-P300-BRD4 axis

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 lowdensity 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.

Melatonin antagonizes ovarian aging via YTHDF2-MAPK-NF-κB pathway

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.