2. Academic Validation
  3. USP16 S-nitrosylation aggravates coronary microembolization-induced myocardial injury via repressing KDM1A-mediated glutathione homeostasis

USP16 S-nitrosylation aggravates coronary microembolization-induced myocardial injury via repressing KDM1A-mediated glutathione homeostasis

  • Nat Commun. 2025 Dec 3;17(1):255. doi: 10.1038/s41467-025-66943-x.
Qiang Su 1 2,  Jiao-Qin Qin 3,  Yuan Huang 2,  Ri-Xin Dai 4,  Qing-Yun Wu 4,  Li-Rong Mo 5,  Qiang Wu 6,  Wan-Zhong Huang 7,  Hua-Feng Yang 8,  Yang-Chun Liu 8,  Di-Guang Pan 9
Affiliations

Affiliations

  • 1 Department of Cardiology, Guilin People's Hospital, Guilin, Guangxi, China.
  • 2 Department of Cardiology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China.
  • 3 Department of Neurology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China.
  • 4 Department of Cardiology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
  • 5 Department of Cardiology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China. [email protected].
  • 6 Senior Department of Cardiology, the Sixth Medical Center, Chinese PLA General Hospital, Beijing, China. [email protected].
  • 7 Department of Cardiology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China. [email protected].
  • 8 Cardiothoracic Surgery Intensive Care Unit, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
  • 9 Department of Cardiology, Guilin People's Hospital, Guilin, Guangxi, China. [email protected].
PMID: 41339351 DOI: 10.1038/s41467-025-66943-x
Abstract

Coronary microembolization (CME) is a serious cardiovascular complication that causes severe cardiac dysfunction and arrhythmias. Glutathione (GSH) exhaustion-induced oxidative stress is a key contributor to CME. Here, we explore the molecular mechanisms underlying GSH imbalance during CME. We show that CME induces myocardial injury by disturbing GSH homeostasis, which is ameliorated by glutamate-cysteine Ligase modifier subunit (GCLM) or Glutaminase (GLS) overexpression. Lysine-specific Histone Demethylase 1A (KDM1A) removes H3K9me1/2 from the promoter regions of GCLM and GLS to promote their epigenetic expression, thereby maintaining GSH homeostasis in CME. KDM1A is ubiquitinated at the K355 site during CME via inhibiting ubiquitin-specific peptidase 16 (USP16)-mediated deubiquitination. Inducible nitric oxide synthase (iNOS) facilitates S-nitrosylation (SNO) of USP16 at the C731 site, contributing to KDM1A ubiquitination and causing GSH imbalance during CME. Altogether, SNO-USP16 inhibition stabilizes the KDM1A protein to epigenetically activate GCLM and GLS, thus maintaining GSH homeostasis and relieving CME-induced myocardial injury.

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