Cystine import and oxidative catabolism fuel vascular growth and repair via nutrient-responsive histone acetylation
Endothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine de novo biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration.
Authors
- Harald F. Langer (ORCID: https://orcid.org/0000-0003-2224-0518)
- Stephan Klatt (ORCID: https://orcid.org/0000-0003-0064-3367)
- Christian Koch (ORCID: https://orcid.org/0000-0002-2655-7363)
- Fredy Delgado Lagos (ORCID: https://orcid.org/0000-0003-2096-9858)
- Jiong Hu (ORCID: https://orcid.org/0000-0001-8266-0886)
- Christoph Plass (ORCID: https://orcid.org/0000-0003-2554-3952)
- James A. Oo (ORCID: https://orcid.org/0000-0002-2934-7580)
- Yifang Mao
- Andreas Weigert (ORCID: https://orcid.org/0000-0002-7529-1952)
- Sofia‐Iris Bibli (ORCID: https://orcid.org/0000-0001-7153-6628)
- Dennis Hecker (ORCID: https://orcid.org/0000-0003-0272-243X)
- Marion Bähr (ORCID: https://orcid.org/0009-0000-2942-0701)
- Joerg Heineke (ORCID: https://orcid.org/0000-0002-1541-3030)
- Mauro Siragusa (ORCID: https://orcid.org/0000-0002-5862-5156)
- Jeanette Eresch (ORCID: https://orcid.org/0000-0002-9310-2633)
- Dieter Weichenhan (ORCID: https://orcid.org/0000-0002-7915-412X)
- Mahak Singhal (ORCID: https://orcid.org/0000-0002-7303-9585)
- Gergana D. Dobreva (ORCID: https://orcid.org/0000-0002-4814-9416)
- Julio Cordero (ORCID: https://orcid.org/0000-0002-2136-1783)
- Stefan Günther (ORCID: https://orcid.org/0000-0002-5594-4549)
- Andreas Papapetropoulos (ORCID: https://orcid.org/0000-0002-4253-5930)
- Janina Wittig (ORCID: https://orcid.org/0009-0002-6091-7569)
- Marcel H. Schulz (ORCID: https://orcid.org/0000-0002-1252-3656)
- Ralf P. Brandes (ORCID: https://orcid.org/0000-0002-8035-0048)
- Maria-Kyriaki Drekolia
- Mario Looso (ORCID: https://orcid.org/0000-0003-1495-9530)
- Boran Zhang (ORCID: https://orcid.org/0000-0003-4323-8732)
- Ingrid Fleming (ORCID: https://orcid.org/0000-0003-1881-3635)
- Janina Mettner
- Xiaoming Li (ORCID: https://orcid.org/0000-0002-0931-727X)
- H. Cui (ORCID: https://orcid.org/0000-0002-9923-1313)
- Daiyu Wang
Institutions
- Goethe University Frankfurt (DE)
- German Cancer Research Center (DE)
- Academy of Athens (GR)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Medical Centre Mannheim (DE)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1016/j.cmet.2025.10.003
- Citations
- 1
- Primary Topic
- Biomedical Research and Pathophysiology
- Type
- article
- Field-Weighted Citation Impact
- 1.47