Kaposi's sarcoma-associated herpesvirus（KSHV）是一个由潜伏和溶解生命周期组成的致癌病毒。原始积水淋巴瘤（PEL）是一种侵袭性B细胞系淋巴瘤，主要被KSHV潜伏感染。KSHV的潜伏感染是持续存在的，对消灭肿瘤细胞构成了障碍。与消除潜伏HIV库的“震荡杀灭”策略类似，诱导病毒溶解性复活的方法代表了一种独特的抗肿瘤策略，因为它有可能增加对癌症的细胞毒性的特异性。受到这一观念的启发，我们提出了从潜伏中诱导KSHV溶解性复活可能是KSHV相关癌症的潜在治疗策略。氧化应激，PEL的临床特征之一，是最主要的KSHV复活诱导剂之一。然而，令人矛盾的是，我们发现过氧化氢（H2O2）在剂量依赖的方式上对KSHV阴性 B 淋巴瘤细胞触发了强大的细胞毒性效应，而对KSHV阳性细胞的影响较小。从机制上讲，我们确定了forkhead box蛋白O1（FoxO1）和FoxO3作为不可逆的抗氧化防御基因，且它们的上调是由KSHV潜伏感染所致，这对于促进KSHV阳性B淋巴瘤细胞中的ROS清除是必要的。药物抑制或功能性沉默FoxO1或FoxO3中的任何一个就足以消除其抗氧化能力，从而增加细胞内ROS水平，进一步将KSHV从潜伏状态逆转为活跃的溶解复制，在体外和体内导致巨大的细胞死亡。此外，通过抑制FoxO蛋白增加ROS水平，进一步使PEL细胞对ROS诱导的凋亡更加敏感。因此，我们的研究证明了通过抑制FoxO蛋白来诱导KSHV的溶解性复活是PEL的一种有前景的治疗方法，这一方法还可以进一步拓展到其他病毒相关的疾病。 版权所有：© 2023 Lan et al. 本文为开放获取文章，在原作者和来源被标注的情况下，允许在任何媒介中进行无限制的使用、分发和复制。

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus consisting of both latent and lytic life cycles. Primary effusion lymphoma (PEL) is an aggressive B-cell lineage lymphoma, dominantly latently infected by KSHV. The latent infection of KSHV is persistent and poses an obstacle to killing tumor cells. Like the "shock and kill" strategy designed to eliminate latent HIV reservoir, methods that induce viral lytic reactivation in tumor latently infected by viruses represent a unique antineoplastic strategy, as it could potentially increase the specificity of cytotoxicity in cancer. Inspired by this conception, we proposed that the induction of KSHV lytic reactivation from latency could be a potential therapeutic stratagem for KSHV-associated cancers. Oxidative stress, the clinical hallmark of PEL, is one of the most prominent inducers for KSHV reactivation. Paradoxically, we found that hydrogen peroxide (H2O2) triggers robust cytotoxic effects on KSHV-negative rather than KSHV-positive B lymphoma cells in a dose-dependent manner. Mechanistically, we identified forkhead box protein O1 (FoxO1) and FoxO3 as irrevocable antioxidant defense genes and both of them are upregulated by KSHV latent infection, which is essential for the promoted ROS scavenging in KSHV-positive B lymphoma cells. Pharmacological inhibition or functional knockdown of either FoxO1 or FoxO3 is sufficient to ablate the antioxidant ability and therefore increases the intracellular ROS level that further reverses KSHV from latency to active lytic replication in PEL cells, resulting in tremendous cell death both in vitro and in vivo. Additionally, the elevated level of ROS by inhibiting FoxO proteins further sensitizes PEL cells to ROS-induced apoptosis. Our study therefore demonstrated that the lytic reactivation of KSHV by inhibiting FoxO proteins is a promising therapeutic approach for PEL, which could be further extended to other virus-associated diseases.Copyright: © 2023 Lan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.