A recently published article in Nature Communications (https://www.nature.com/articles/s41467-025-66943-x) by Dr. Qiang Su and colleagues reports a novel molecular pathway that intensifies myocardial injury following coronary microembolization (CME). The researchers demonstrate that chemical modification of the deubiquitinase USP16 disrupts antioxidant regulation by destabilizing a key metabolic enzyme, ultimately worsening oxidative damage, and impairing cardiac function.
"CME occurs when microvascular obstruction develops due to embolic debris originating from plaque rupture or percutaneous interventions. This occlusion of small coronary vessels triggers oxidative stress, microinfarction, and a decline in ventricular performance," explained Qiang Su, professor in the Department of Cardiology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, China. He added that although replenishing glutathione (GSH) has been recognized as protective, the mechanisms that suppress endogenous GSH biosynthesis during CME have remained poorly understood.
The study identifies lysine-specific histone demethylase 1A (KDM1A) as a central regulator of intracellular GSH production. Under normal physiological conditions, KDM1A promotes transcription of enzymes required for GSH synthesis. However, both animal models of CME and hypoxia-induced cardiomyocyte models showed a notable reduction in KDM1A protein levels during myocardial injury.
KDM1A loss occurs due to increased ubiquitin-dependent degradation. Normally, KDM1A turnover is balanced by RNF138, an E3 ubiquitin ligase, and USP16, a deubiquitinase. USP16 stabilizes KDM1A by removing ubiquitin tags, which supports GSH biosynthesis. In CME, this stabilization is disrupted.
"We discovered that USP16 undergoes S-nitrosylation at cysteine 731, a modification mediated by inducible nitric oxide synthase (iNOS). This post-translational modification inactivates USP16, allowing RNF138-mediated ubiquitination of KDM1A to proceed unchecked," stated Di-Guang Pan, senior cardiologist at the Department of Cardiology, Guilin People's Hospital, Guangxi, China. He emphasized that the resulting degradation of KDM1A suppresses transcriptional activity needed for glutathione synthesis, leading to diminished antioxidant capacity, accumulation of reactive oxygen species, mitochondrial impairment, and more extensive myocardial necrosis.
"Key experimental findings indicated that rat models of CME showed increased S-nitrosylated USP16, decreased KDM1A expression, and reduced GSH levels. Overexpressing KDM1A or preventing its degradation helped maintain myocardial function and redox balance, while reducing infarct size." said Qiang Wu, from the Senior Department of Cardiology, the Sixth Medical Center, Chinese PLA General Hospital, Beijing, China.
Mutating the S-nitrosylation site on USP16 inhibited KDM1A degradation and lessened myocardial injury. Additionally, inhibiting iNOS with 1400W reduced USP16 nitrosylation, stabilized KDM1A, and improved cardiac outcomes. This work outlines a pathological cascade in CME: iNOS induction → USP16 S-nitrosylation → KDM1A degradation → impaired GSH synthesis → myocardial injury
The authors suggest that strategies to prevent USP16 S-nitrosylation or preserve KDM1A stability could help maintain antioxidant balance and reduce cardiac injury associated with CME.
