伏立诺他 (SAHA) 是一种组蛋白脱乙酰酶抑制剂，已显示出对晚期皮肤 T 细胞淋巴瘤 (CTCL) 的临床疗效。然而，只有一小部分 CTCL 患者 (30-35%) 对 SAHA 有反应，而且这种反应并不总是可持续的。因此，了解这种癌症逃避耐药的机制是提高当前疗法疗效的未满足的医学需求。本研究旨在确定导致 CTCL 中 SAHA 耐药的因素以及减轻这种耐药的方法。在这项研究中，我们证明了减弱的活性氧 (ROS) 会诱导白细胞介素 (IL)-2Rα（IL-2 受体之一）的表达，从而驱动 CTCL 对 SAHA 的抵抗。我们还确定斑蝥素可以通过 ROS 依赖性方式阻断 IL-2Rα 相关信号传导来克服 SAHA 对 CTCL 的耐药性。从机制上讲，SAHA 耐药 CTCL 中 ROS 水平降低，导致 IL-2Rα 翻译加速导致 IL-2Rα 蛋白过度形成。同时，IL-2Rβ 与 IL-2Rγ 和 Janus 激酶/信号转导器和转录分子激活剂的相互作用增强，以及蛋白激酶 B (AKT)/mTOR 和丝裂原表达增加，证明了 IL-2R 信号的放大。 -激活蛋白激酶信号传导。此外，中药斑蝥中的活性成分斑蝥素可显着提高ROS水平，从而抑制IL-2Rα翻译，从而抑制SAHA耐药细胞的下游通路。斑蝥素还被发现与 SAHA 具有协同作用，并在体外和体内通过 IL-2R 信号触发 SAHA 抗性细胞死亡。我们的研究揭示了获得性 SAHA 抗性的新分子机制，并表明使用斑蝥素是克服 SAHA 抗性的潜在方法CTCL 治疗耐药。我们的研究结果证明了斑蝥素在治疗 CTCL 方面的治疗潜力。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。由英国医学杂志出版。

Vorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30-35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies.This study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it.In this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance to SAHA in CTCL. We also determined that cantharidin could overcome SAHA resistance to CTCL by blocking IL-2Rα-related signaling via ROS-dependent manner. Mechanistically, accelerated translation of IL-2Rα contributes to excessive IL-2Rα protein formation as a result of reduced ROS levels in SAHA-resistant CTCL. At the same time, amplified IL-2R signals are evidenced by strengthened interaction of IL-2Rβ with IL-2Rγ and Janus kinase/signal transducer and activator of transcription molecules, and by increased expression of protein kinase B (AKT)/mTOR and mitogen-activated protein kinase signaling. Moreover, cantharidin, an active constituent of Mylabris used in traditional Chinese medicine, markedly increased ROS levels, and thereby restrained IL-2Rα translation, resulting in suppression of downstream pathways in SAHA-resistant cells. Cantharidin is also found to synergize with SAHA and triggers SAHA-resistant cell death via IL-2R signaling both in vitro and in vivo.Our study uncovers a novel molecular mechanism of acquired SAHA resistance and also suggests that using cantharidin is a potential approach to overcome CTCL therapy resistance. Our findings underlie the therapeutic potential of cantharidin in treating CTCL.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.