越来越多的证据表明，在肿瘤发生、增殖、转移和治疗抵抗方面，DDX5（也称为p68）作为主调节因子和潜在的生物标记和靶点发挥着重要作用。然而，DDX5也被报道为一个抑癌基因。这些似乎矛盾的观察可以通过DDX5在DNA修复中的作用来解释。这是因为癌细胞凋亡和恶性转化可能代表由DDX5调节的单一过程的两种可能结果，反映了不同强度的DNA损伤。因此，靶向DDX5可能会将癌细胞从生长抑制状态（DNA修复必需）转变为凋亡和细胞杀伤状态。除了越来越多的研究证实了DDX5在全基因组稳定监测和DNA损伤修复中的作用之外，还发现DDX5在多条致癌信号通路中有着重要作用。DDX5似乎通过与不同类型的组织/细胞中独特蛋白的相互作用，利用不同的信号级联发挥着相反的作用（例如，在平滑肌细胞和癌细胞中）。这些独特的特点使得DDX5成为治疗人类癌症的一个有趣的治疗靶点，对正常组织毒性较低。在本综述中，我们讨论了DDX5在癌症中DNA修复、免疫抑制、致癌代谢重构、病毒感染促进和对人类微生物群（菌群）的负面影响方面的多方面功能。我们还提供了新的数据，显示FL118，一种分子胶DDX5降解剂，对当前具有治疗抵抗性的前列腺癌器官样体/细胞具有选择性作用。总之，当前的研究表明，DDX5可能代表一种对癌症有效征战的独特鳍靶，对正常组织毒性最小。©2023年. 伊利诺伊国家癌症研究所“Regina Elena”。

There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and a potential biomarker and target, in tumorigenesis, proliferation, metastasis and treatment resistance for cancer therapy. However, DDX5 has also been reported to act as an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5's role in DNA repair. This is because cancer cell apoptosis and malignant transformation can represent the two possible outcomes of a single process regulated by DDX5, reflecting different intensity of DNA damage. Thus, targeting DDX5 could potentially shift cancer cells from a growth-arrested state (necessary for DNA repair) to apoptosis and cell killing. In addition to the increasingly recognized role of DDX5 in global genome stability surveillance and DNA damage repair, DDX5 has been implicated in multiple oncogenic signaling pathways. DDX5 appears to utilize distinct signaling cascades via interactions with unique proteins in different types of tissues/cells to elicit opposing roles (e.g., smooth muscle cells versus cancer cells). Such unique features make DDX5 an intriguing therapeutic target for the treatment of human cancers, with limited low toxicity to normal tissues. In this review, we discuss the multifaceted functions of DDX5 in DNA repair in cancer, immune suppression, oncogenic metabolic rewiring, virus infection promotion, and negative impact on the human microbiome (microbiota). We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues.© 2023. Italian National Cancer Institute ‘Regina Elena’.