Ciclopirox (CPX), a well-established antifungal agent, has recently emerged as a promising candidate for drug repurposing in oncology because of its broad-spectrum antitumour properties. This study aimed to elucidate the mechanisms underlying the antitumour activity CPX in hepatocellular carcinoma (HCC) and evaluate its potential as a repurposed therapeutic agent. In this study, comprehensive in vitro and in vivo experiments were conducted using HCC models. In vitro, cell cycle progression, migration, and invasion were evaluated following CPX treatment. The levels of NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis and reactive oxygen species (ROS) production were measured to explore the underlying molecular mechanisms. In vivo, CPX was administered to nude mice bearing liver cancer xenografts to assess its tumour-suppressive effects. Mechanistic studies focused on ROS-mediated NLRP3 activation and its role in pyroptosis, including Caspase-1 activation and gasdermin D (GSDMD) cleavage. The results showed that CPX induced cell cycle arrest and markedly inhibited HCC cell migration and invasion. These effects were associated with the upregulation of NLRP3 expression and increased ROS production, leading to oxidative stress. In vivo, CPX administration suppressed the growth of liver cancer xenografts. Mechanistically, the antitumour activity of CPX was dependent on the ROS-mediated activation of NLRP3-regulated pyroptosis, which is characterized by Caspase-1 activation and GSDMD cleavage. In conclusion, CPX exerts its antitumour effects on HCC through ROS-dependent NLRP3-mediated pyroptosis. This study provides a strong rationale for further clinical exploration and development of CPX-based therapies, offering a promising avenue for improving outcomes in patients with HCC.
Keywords: Ciclopirox olamine; HCC; NLRP3; Pyroptosis; ROS.
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