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.

Nitidine chloride (NC) 是中药Zanthoxylum nitidum的标准活性成分(Roxb.) DC。(ZN)。NC 已显示出多种药理活性，包括抗肿瘤活性。由于许多抗肿瘤药物会引起心脏毒性，在此我们研究了 NC 是否发挥心脏毒性作用及其潜在机制。ZN (ZNE) 的水提取物被腹膜内注射到大鼠体内，而 NC 被注射到比格犬和小鼠体内，每天一次，持续 4 周。使用超声心动图评估心功能。我们表明，在大鼠中给药的 ZNE 和在小鼠中给药的 NC 都会引起剂量依赖性心脏肥大和功能障碍，而中剂量和高剂量的 NC 会导致 Beagles 死亡。一致地，我们观察到 NC 处理的小鼠和新生小鼠心肌细胞的心脏自噬水平降低。此外，我们证明自噬相关的 4B 半胱氨酸肽酶 (ATG4B) 可能是 NC 的潜在靶标，因为 ATG4B 的过表达逆转了心脏肥大并降低了在 NC 处理的小鼠中观察到的自噬水平。我们得出结论，NC 通过 ATG4B 介导的小鼠自噬下调诱导心脏肥大。因此，本研究为ZN的安全临床应用和NC作为抗肿瘤药物的使用提供了指导。