Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase

Yang Hong1, Wan-qing Xu1, Jing Feng1, Han Lou1, Heng Liu1, Lei Wang1, Hao Cui1, Lin-tong Jiang1, Ran-chen Xu1, Heng-hui Xu1, Min-zhen Xie2, Yang Li3, Philipp Kopylov4, Qi Wang2, Yong Zhang1,5,6
1 Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
2 Department of Medicinal Chemistry and Natural Medicinal Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China
3 Department of Pharmaceutical Analysis, College of Pharmacy, Harbin Medical University, Harbin 150081, China
4 Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow 101-135, Russian Federation
5 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin 150081, China
6 Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin 150086, China
Correspondence to: Qi Wang:, Yong Zhang:,
DOI: 10.1038/s41401-022-00968-6
Received: 15 March 2022
Accepted: 25 July 2022
Advance online: 19 August 2022


Nitidine chloride (NC) is a standard active component from the traditional Chinese medicine Zanthoxylum nitidum (Roxb.) DC. (ZN). NC has shown a variety of pharmacological activities including anti-tumor activity. As a number of anti-tumor drugs cause cardiotoxicity, herein we investigated whether NC exerted a cardiotoxic effect and the underlying mechanism. Aqueous extract of ZN (ZNE) was intraperitoneally injected into rats, while NC was injected into beagles and mice once daily for 4 weeks. Cardiac function was assessed using echocardiography. We showed that both ZNE administered in rats and NC administered in mice induced dose-dependent cardiac hypertrophy and dysfunction, whereas administration of NC at the middle and high dose caused death in Beagles. Consistently, we observed a reduction of cardiac autophagy levels in NC-treated mice and neonatal mouse cardiomyocytes. Furthermore, we demonstrated that autophagy-related 4B cysteine peptidase (ATG4B) may be a potential target of NC, since overexpression of ATG4B reversed the cardiac hypertrophy and reduced autophagy levels observed in NC-treated mice. We conclude that NC induces cardiac hypertrophy via ATG4B-mediated downregulation of autophagy in mice. Thus, this study provides guidance for the safe clinical application of ZN and the use of NC as an anti-tumor drug.

Keywords: cardiac hypertrophy; nitidine chloride; Zanthoxylum nitidum (Roxb.) DC; autophagy; autophagy-related 4B cysteine peptidase; species-based differences

Article Options

Download Citation

Cited times in Scopus