Abstract：
Liver cancer stands as the fourth leading global cause of death, and its prognosis remains grim due to the limited effectiveness of current medical interventions. Among the various pathways implicated in the development of hepatocellular carcinoma (HCC), the hedgehog signaling pathway has emerged as a crucial player. Itraconazole, a relatively safe and cost-effective antifungal medication, has gained attention for its potential as an anticancer agent. Its primary mode of action involves inhibiting the hedgehog pathway, yet its impact on HCC has not been elucidated. The main objective of this study was to investigate the effect of itraconazole on diethylnitrosamine-induced early-stage HCC in rats. Our findings revealed that itraconazole exhibited a multifaceted arsenal against HCC by downregulating the expression of key components of the hedgehog pathway, shh, smoothened (SMO), and GLI family zinc finger 1 (GLI1), and GLI2. Additionally, itraconazole extended survival and improved liver tissue structure, attributed mainly to its inhibitory effects on hedgehog signaling. Besides, itraconazole demonstrated a regulatory effect on Notch1, and Wnt/β-catenin signaling molecules. Consequently, itraconazole displayed diverse anticancer properties, including anti-inflammatory, antiangiogenic, antiproliferative, and apoptotic effects, as well as the potential to induce autophagy. Moreover, itraconazole exhibited a promise to impede the transformation of epithelial cells into a more mesenchymal-like phenotype. Overall, this study emphasizes the significance of targeting the hedgehog pathway with itraconazole as a promising avenue for further exploration in clinical studies related to HCC treatment.
摘要：
肝癌是全球第四大死因。由于当前医疗干预措施的有效性有限，其预后仍然严峻。在涉及肝细胞癌（HCC）发展的各种途径中，刺猬信号通路已经成为一个关键的参与者。伊曲康唑,一种相对安全且具有成本效益的抗真菌药物，因其作为抗癌药物的潜力而受到关注。其主要作用方式包括抑制刺猬通路,但其对HCC的影响尚未阐明。本研究的主要目的是研究伊曲康唑对二乙基亚硝胺诱导的大鼠早期HCC的影响。我们的发现表明，伊曲康唑通过下调hedgehog途径的关键成分的表达表现出多方面的抗HCC的武器库，嘘,平滑(SMO)，和GLI系列锌指1（GLI1），和GLI2。此外,伊曲康唑延长生存和改善肝组织结构，主要归因于其对刺猬信号的抑制作用。此外,伊曲康唑对Notch1和Wnt/β-catenin信号分子具有调节作用。因此,伊曲康唑表现出不同的抗癌特性，包括消炎药,抗血管生成,抗增殖,和凋亡效应，以及诱导自噬的潜力。此外，伊曲康唑有望阻止上皮细胞转化为更多的间充质样表型。总的来说,这项研究强调了伊曲康唑靶向hedgehog途径的重要性,作为进一步探索HCC治疗相关临床研究的一个有希望的途径.
