2. Academic Validation
  3. MEK inhibitor induces cardiac complications by preventing ZMYND8-mediated ubiquitination and proteasomal degradation of HMGB1

MEK inhibitor induces cardiac complications by preventing ZMYND8-mediated ubiquitination and proteasomal degradation of HMGB1

  • Biochem Pharmacol. 2025 Dec 19:245:117660. doi: 10.1016/j.bcp.2025.117660.
Huangxi Fu 1,  Feng Jiang 1,  Anqi Xu 1,  Taicheng Zhou 1,  Ning Liu 2,  Xueqin Chen 3,  Zizheng Gao 1,  Wentong Wu 4,  Hao Yan 1,  Xiaochun Yang 1,  Bo Yang 5,  Qiaojun He 6,  Peihua Luo 6,  Zhifei Xu 7
Affiliations

Affiliations

  • 1 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang, PR China.
  • 2 Emergency Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016 Zhejiang, PR China.
  • 3 Thoracic Cancer Department, Hangzhou Cancer Hospital, Hangzhou 310002 Zhejiang, PR China; Department of Medical Oncology, Affiliated Hangzhou First People's Hospital, Xihu University School of Medicine, Hangzhou 310006 Zhejiang, PR China.
  • 4 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018 Zhejiang, PR China.
  • 5 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018 Zhejiang, PR China; School of Medicine, Hangzhou City University, Hangzhou 310015 Zhejiang, PR China; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang, PR China.
  • 6 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018 Zhejiang, PR China; Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 Zhejiang, PR China.
  • 7 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang, PR China. Electronic address: [email protected].
PMID: 41423035 DOI: 10.1016/j.bcp.2025.117660
Abstract

The cardiac complications caused by drugs, including cardiac dysfunction and heart failure, significantly limit the wide clinical application of drugs and lead to morbidity and mortality. High mobility group box 1 (HMGB1) plays an extensive role in drug-induced cardiotoxicity. However, the cardiotoxic mechanisms for most small-molecule kinase inhibitors (SMKIs) remains unknown. Here, we identify that accumulated HMGB1 is associated with the cardiac complications caused by a series of FDA-approved SMKIs, among which trametinib-induced cardiomyocyte death was most significantly reversed by HMGB1 knockout. Moreover, cardiomyocyte-specific Hmgb1 deletion in mice could improve cardiac muscle contraction, calcium regulation and cardiomyocyte Apoptosis in autophagy- or inflammation-independent manner. We further show that trametinib leads to the aberrant accumulation of HMGB1 by increasing its stability via inhibiting Zinc Finger Protein Zinc Finger MYND-Type Containing 8 (ZMYND8)-mediated ubiquitination and proteasomal degradation of HMGB1, identifying ZMYND8 as a novel negative regulator of HMGB1 stability in cardiomyocyte and a potential novel regulator of cardiac function. Glycyrrhizic acid, an HMGB1 inhibitor used in clinic, prevents trametinib-induced cardiac complications. These findings reveal the mechanism and propose an effective intervention strategy for trametinib-induced cardiac complications, which would contribute to the safe application of trametinib, cardiac safety evaluation of drugs or candidate compounds and novel drug development.

Keywords

Cardiac Complications; Glycyrrhizic Acid; HMGB1; Trametinib; ZMYND8.

Figures
Products