Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1β inhibition. SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

中文翻译：

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肝细胞癌中 SIRT7 的抑制通过 DDX3X 介导的 NLRP3 炎性体抑制 ERK1/2 磷酸化来克服索拉非尼获得性耐药

Sirtuin 7 (SIRT7) 在肿瘤发展中发挥着重要作用，并被认为是细胞应激的有效调节剂。然而，SIRT7 对索拉非尼获得性耐药的影响仍不清楚，并且 HCC 中除此过程之外的可能抗肿瘤机制尚未阐明。我们检查了 SIRT7 的治疗潜力，并确定它是否与索拉非尼具有协同作用以克服化疗耐药性。使用癌症基因组图谱-肝脏 HCC 数据和无偏基因集富集分析来确定 SIRT7 作为索拉非尼获得性耐药的潜在效应分子。开发了两种类型的 SIRT7 化学抑制剂来评估其与索拉非尼协同作用时的治疗特性。进行质谱分析以发现 SIRT7、DDX3X 的直接靶标，并探讨了 DDX3X 脱乙酰水平和蛋白质稳定性。此外，还利用体内异种移植模型证实了SIRT7和DDX3X化学抑制剂联合索拉非尼的抗肿瘤作用。SIRT7 抑制介导的 DDX3X 耗竭可以通过破坏 NLRP3 炎性体组装来重新敏感获得性索拉非尼耐药，最终抑制对 NLRP3 炎性体介导的 IL-1β 抑制反应的过度活跃的 ERK1/2 信号传导。SIRT7 负责索拉非尼获得性耐药，当与索拉非尼联合使用时，通过抑制过度活跃的亲细胞存活 ERK1/2 信号传导，对其进行抑制将是有益的。