SUMOylation plays a crucial role in regulating gene expression by promoting interactions between transcription factors and corepressors. Daxx, a multifunctional scaffold protein, specifically recognizes and binds SUMOylated transcription factors through its SUMO-interacting motifs (SIMs), acting as a transcriptional corepressor. In this review, we systematically elucidate the structural basis of the interaction between Daxx and SUMO, revealing the synergistic mechanism by which Daxx SIM phosphorylation and SUMO acetylation dynamically regulate Daxx function. In promyelocytic leukemia nuclear bodies (PML NBs), phosphorylation of Daxx’s SIM enhances its binding to SUMOylated PML, leading to the sequestration and inactivation of Daxx within PML NBs. Conversely, SUMO acetylation disrupts the electrostatic interactions between SUMO and SIMs, prompting the release of Daxx from PML NBs and its translocation to the nucleoplasm, where it inhibits the activity of transcription factors such as ETS1, GR, and SMAD4. Daxx SIMs are common binding sites for the interaction between SUMOylated transcription factors and Daxx, and different SUMOylated transcription factors may compete to bind to Daxx, which cross-regulates cellular life activities. This mechanism highlights the dynamic regulation of Daxx subcellular localization and transcriptional repression by SUMO and PML NBs, providing valuable insights into understanding Daxx-mediated transcriptional repression.

Atherosclerosis (AS), a chronic cardiovascular disease, originates from endothelial dysfunction, a process closely linked to cellular energy metabolism. While rosmarinic acid (RA) exhibits protective cardiovascular effects, its precise mechanism against AS remains undefined. This study demonstrates that RA alleviates AS in ApoE^−/− mice, as evidenced by reduced aortic plaques, enhanced CD31 expression, and improved serum NO and ET-levels. Integrating network pharmacology and experimental validation, we identified Aldo-keto reductase family 1 member B1 (AKR1B1) as a direct functional target of RA. Mechanistically, RA downregulated AKR1B1, thereby activating the SIRT3/PFKFB3 axis. In Ox-LDL-induced HUVECs, RA enhanced viability, reduced ROS, and boosted energy metabolism, indicated by elevated ECAR, OCR, and levels of G-6-P, F-6-P, and ATP. Crucially, RA rescued endothelial injury induced by AKR1B1 overexpression via this pathway. Our findings establish that RA protects against AS by directly targeting AKR1B1 to restore endothelial energy homeostasis through the AKR1B1/SIRT3/PFKFB3 signaling axis, offering a novel therapeutic strategy.

Objectives: Endothelial apoptosis is a central event in atherosclerotic vascular injury, yet the contribution of the INO80 chromatin-remodeling subunit INO80E to this process remains unclear. This study examined whether INO80E is altered during atherosclerosis (AS)-associated endothelial injury and explored its functional role in ox-LDL-triggered apoptosis. Methods: Atherosclerotic mouse models were used to examine INO80E expression in vascular tissues, and ox-LDL-treated HUVECs were applied as an in vitro model of endothelial injury. The functional role of INO80E was evaluated using lentiviral overexpression and siRNA-mediated knockdown approaches, while apoptosis was measured by flow cytometry and TUNEL staining. Mechanistic experiments included co-immunoprecipitation, immunofluorescence, YY1 acetylation analysis, and pharmacological inhibition with the pan-HDAC inhibitor trichostatin A (TSA). In addition, YY1-silencing rescue experiments were performed in INO80E-overexpressing cells to determine whether YY1 contributes to the protective effect of INO80E against ox-LDL-induced endothelial apoptosis. Results: INO80E expression was reduced in the endothelial layer of ApoE^−/− aortas and in ox-LDL-treated HUVECs. INO80E overexpression attenuated ox-LDL-induced apoptosis and increased the Bcl-2/BAX ratio, whereas INO80E knockdown produced the opposite effect. INO80E colocalized with HDAC1, increased the HDAC1-YY1 association, decreased YY1 acetylation, and prolonged YY1 protein stability. TSA treatment weakened the anti-apoptotic phenotype associated with INO80E overexpression, and rescue experiments showed that YY1 knockdown partially reversed the INO80E overexpression-associated regulation of Bcl-2 and BAX. Conclusions: These findings suggest that INO80E protects endothelial cells from ox-LDL-induced apoptosis, at least in part by promoting HDAC-associated YY1 deacetylation and stabilization. The INO80E-HDAC1-YY1 pathway may represent a candidate protective mechanism in AS that requires further validation.