Abstract
Hydrogen sulfide (H₂S), generated by cystathionine γ-lyase (CSE), protects against aortic aneurysm and dissection (AAD), yet its role in extracellular matrix (ECM) regulation remains unclear. Here, we demonstrate that CSE expression is markedly attenuated in vascular smooth muscle cells (VSMCs) from human AAD specimens and AngII-induced male murine models. VSMC-specific Cse deletion exacerbated AAD formation. Mechanistically, Cse deficiency downregulated CBX3, thereby relieving transcriptional repression of Adamts4. Cbx3 overexpression rescued the aggravated AAD phenotype in Cse-deficient male mice. We further identified a CBX3-centered epigenetic complex (SUV39H1, KDM2A, HDAC1, RING1) that coordinates H3K9/4 methylation and acetylation to regulate ECM remodeling, apoptosis and inflammation-related genes. Notably, CSE/H₂S induced CBX3 sulfhydration at C69, C160, and C177, enhancing protein stability by reducing ubiquitin-mediated degradation; Therapeutically, AAV-mediated Cse or Cbx3 delivery via an extravascular carrier attenuated AAD incidence and progression in male mice. Collectively, these findings define a VSMCs CSE/H₂S-CBX3 epigenetic axis that constrains AAD through regulation of the ADAMTS4-versican pathway.
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We thank He Wu and Zengxiang Dong for their help in offering human’s slices.
Funding
This work was supported by grants from the Natural Science Foundation of China (U24A20650, 82370448, 82100492, and 82370315); the State Key Laboratory of Frigid Zone Cardiovascular Diseases, Ministry of Science and Technology, Open Subject (HDHY2024010); the Special project funded by the Ministry of Science and Technology of China (2024GZkf-03); the Key Laboratory of Myocardial Ischemia, Ministry of Education (KF202402) and Heilongjiang Province Spring Swallow Support Project (CYCX24007).
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Zhao, Y., Cui, C., Gao, H. et al. Chromobox 3 assembles an epigenetic complex contributing to cystathionine γ-lyase–mediated protection against aortic aneurysm/dissection. Nat Commun (2026). https://doi.org/10.1038/s41467-026-74048-2
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DOI: https://doi.org/10.1038/s41467-026-74048-2
