反应性氧化物（ROS）是一类高度短寿命分子，控制着细胞的多种行为。正常细胞维持ROS平衡以确保其功能。由于致癌应激，癌细胞经常具有过多的ROS，也称为氧化应激，通常通过增强抗氧化剂系统来抵消，以维持氧化还原平衡。与Kaposi肉瘤(KS)有关的致癌病毒Kaposi肉瘤相关的疱疹病毒(KSHV)表现出高度炎症和氧化应激作为标志。我们先前表明过多的ROS可以通过诱导病毒裂解性复制来破坏KSHV潜伏期，导致细胞死亡。然而，大多数KS肿瘤细胞在高度炎症和氧化应激的肿瘤微环境中潜伏性感染KSHV，这部分是由于激活替代补体和TLR4通路，表明KS肿瘤细胞存在增强的抗氧化防御系统。在本研究中，我们展示了KSHV通过劫持forkhead box protein O1 (FoxO1)上调抗氧化基因，包括SOD2和CAT，以维持细胞内ROS水平。此外，KSHV转化细胞内ROS水平的微调平衡对细胞生存至关重要。因此，KSHV转化细胞对外源性ROS进攻非常敏感，如低浓度的过氧化氢（H2 O2）的处理。化学抑制或通过siRNA靶向沉默FoxO1都会降低抗氧化基因的表达，并随后增加KSHV转化细胞内ROS水平，导致细胞增殖和软琥珀中的集落形成的抑制。在机械上，KSHV编码的microRNAs和vFLIP通过激活NF-κB通路上调FoxO1。这些结果揭示了一种新的机制，通过上调FoxO1来对抗氧化应激的致癌病毒，这对于KSHV诱导的细胞增殖和细胞转化是必不可少的。因此，FoxO1可能是KSHV相关恶性肿瘤的一个潜在治疗靶标。本文受版权保护。保留所有权利。

Reactive oxygen species (ROS) are a group of a highly short-lived molecules that control diverse behaviors of cells. Normal cells maintain ROS balance to ensure their functions. Because of oncogenic stress, cancer cells often have excessive ROS, also known as oxidative stress, which are often counteracted by enhanced antioxidant systems in order to maintain redox homeostasis. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with Kaposi's sarcoma (KS), which manifests hyper inflammation and oxidative stress as the hallmarks. We have previously shown that excessive ROS can disrupt KSHV latency by inducing viral lytic replication, leading to cell death. Paradoxically, most KS tumor cells are latently infected by KSHV in a highly inflammatory and oxidative stress tumor microenvironment, which is in part due to the activation of alternative complement and TLR4 pathways, indicating the existence of an enhanced antioxidant defense system in KS tumor cells. In this study, we show that KSHV upregulates antioxidant genes, including SOD2 and CAT by hijacking the forkhead box protein O1 (FoxO1), to maintain intracellular ROS level. Moreover, the fine-tuned balance of ROS level in KSHV-transformed cells is essential for cell survival. Consequently, KSHV-transformed cells are extremely sensitive to exogenous ROS insult such as treatment with a low level of hydrogen peroxide (H2 O2 ). Either chemical inhibition or knockdown of FoxO1 by siRNAs decreases the expression of antioxidant genes and subsequently increases the intracellular ROS level in KSHV-transformed cells, resulting in the inhibition of cell proliferation and colony formation in soft agar. Mechanistically, KSHV-encoded microRNAs and vFLIP upregulate FoxO1 by activating the NF-κB pathway. These results reveal a novel mechanism by which an oncogenic virus counteracts oxidative stress by upregulating FoxO1, which is essential for KSHV-induced cell proliferation and cellular transformation. Therefore, FoxO1 might be a potential therapeutic target for KSHV-related malignancies. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.