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

Qiang Su1,2, Jiao-Qin Qin3, Yuan Huang2

  • 1Department of Cardiology, Guilin People's Hospital, Guilin, Guangxi, China.

Nature Communications
|December 3, 2025
PubMed

Insights

Coronary microembolization (CME) causes heart dysfunction by depleting glutathione (GSH). Inhibiting S-nitrosylated USP16 stabilizes KDM1A, which epigenetically activates GCLM and GLS to restore GSH and protect the heart.

Area of Science:

  • Cardiovascular Science
  • Molecular Biology
  • Epigenetics

Background:

  • Coronary microembolization (CME) is a severe cardiovascular complication linked to cardiac dysfunction and arrhythmias.
  • Glutathione (GSH) depletion and subsequent oxidative stress are key factors contributing to CME-induced myocardial injury.

Purpose of the Study:

  • To elucidate the molecular mechanisms of GSH imbalance during CME.
  • To identify therapeutic targets for mitigating CME-induced cardiac damage.

Main Methods:

  • Investigated the role of glutamate-cysteine ligase modifier subunit (GCLM) and glutaminase (GLS) in maintaining GSH homeostasis during CME.
  • Examined the epigenetic regulation of GCLM and GLS by Lysine-specific histone demethylase 1A (KDM1A).
  • Analyzed the ubiquitination and S-nitrosylation of KDM1A and USP16 in the context of CME.

Main Results:

  • CME disrupts GSH homeostasis, leading to myocardial injury, which is ameliorated by GCLM or GLS overexpression.
  • KDM1A epigenetically activates GCLM and GLS expression by demethylating their promoter regions, maintaining GSH levels.
  • CME induces KDM1A ubiquitination by inhibiting USP16 deubiquitination; inducible nitric oxide synthase (iNOS)-mediated S-nitrosylation of USP16 is crucial for this process.
  • Inhibiting S-nitrosylated USP16 stabilizes KDM1A, reactivates GCLM/GLS, restores GSH homeostasis, and alleviates myocardial injury.

Conclusions:

  • Epigenetic regulation by KDM1A is critical for maintaining GSH homeostasis during CME.
  • Targeting the iNOS-USP16-KDM1A axis offers a novel therapeutic strategy for CME by restoring GSH levels and protecting against cardiac dysfunction.

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