Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide and lacks effective treatment. Herein, we found that the antifungal Natamycin (NAT) exhibits antitumor activity by inducing apoptosis both in vitro and in vivo. Mechanistically, NAT downregulates the expression of Peroxiredoxin 1 (PRDX1) by promoting ubiquitination-mediated degradation, thereby leading to increased reactive oxygen species (ROS) accumulation and subsequent apoptosis. Exogenous overexpression of PRDX1 or N-acetyl-l-cysteine (NAC) pretreatment abrogates NAT-induced cytotoxicity in PLC/PRF/5 and Huh7 cells, suggesting the vital role of ROS in the antitumor properties of NAT. Of note, downregulation of PRDX1 decreases the phosphorylation of AKT, thereby inducing cytoprotective autophagy and combinational use of NAT and chloroquine (CQ) achieves better anti-tumor efficacy. Moreover, NAT acts synergistically with sorafenib (SOR) in HCC suppression. Collectively, our study provides an important molecular basis for NAT-induced cell death and suggests that the antifungal NAT holds the potential to be repurposed as an anticancer drug for HCC treatment.

肝细胞癌 (HCC) 是全球最普遍和最致命的癌症之一，缺乏有效的治疗方法。在此，我们发现抗真菌纳他霉素 (NAT) 通过在体外和体内诱导细胞凋亡而表现出抗肿瘤活性。从机制上讲，NAT 通过促进泛素化介导的降解来下调 Peroxiredoxin 1 (PRDX1) 的表达，从而导致活性氧 (ROS) 积累增加和随后的细胞凋亡。PRDX1或N-乙酰-l的外源过表达-半胱氨酸 (NAC) 预处理消除了 NAT 诱导的 PLC/PRF/5 和 Huh7 细胞的细胞毒性，表明 ROS 在 NAT 的抗肿瘤特性中的重要作用。值得注意的是，PRDX1 的下调会降低 AKT 的磷酸化，从而诱导细胞保护性自噬，并且联合使用 NAT 和氯喹 (CQ) 可获得更好的抗肿瘤功效。此外，NAT 与索拉非尼 (SOR) 在 HCC 抑制中具有协同作用。总的来说，我们的研究为 NAT 诱导的细胞死亡提供了重要的分子基础，并表明抗真菌 NAT 有可能被重新用作 HCC 治疗的抗癌药物。