Interferon (IFN) exerts its effects through interferon-stimulated genes (ISGs), but its efficacy is limited by interferon resistance, which can be caused by the ubiquitination of key proteins. UBE2O was initially identified as a promising therapeutic target based on data from the TCGA and iUUCD 2.0 databases. Through the inhibition of UBE2O, interferon α/β signaling and overall interferon signaling were activated. Integrating data from proteomic, mass spectrometry, and survival analyses led to the identification of IFIT3, a mediator of interferon signaling, as a ubiquitination substrate of UBE2O. The results of in vitro and in vivo experiments demonstrated that the knockdown of UBE2O can enhance the efficacy of interferon-α by upregulating IFIT3 expression. K236 was identified as a ubiquitination site in IFIT3, and the results of rescue experiments confirmed that the effect of UBE2O on interferon-α sensitivity is dependent on IFIT3 activity. ATO treatment inhibited UBE2O and increased IFIT3 expression, thereby increasing the effectiveness of interferon-α. In conclusion, these findings suggest that UBE2O worsens the therapeutic effect of interferon-α by targeting IFIT3 for ubiquitination and degradation.

干扰素 (IFN) 通过干扰素刺激基因 (ISG) 发挥作用，但其功效受到干扰素耐药性的限制，干扰素耐药性可能是由关键蛋白的泛素化引起的。根据 TCGA 和 iUUCD 2.0 数据库的数据，UBE2O 最初被确定为有前途的治疗靶点。通过抑制UBE2O，干扰素α/β信号传导和整体干扰素信号传导被激活。整合蛋白质组学、质谱分析和生存分析的数据，确定了干扰素信号传导介质 IFIT3 作为 UBE2O 的泛素化底物。体外和体内实验结果表明，UBE2O的敲低可以通过上调IFIT3的表达来增强干扰素-α的功效。 K236被确定为IFIT3中的泛素化位点，救援实验的结果证实UBE2O对干扰素-α敏感性的影响依赖于IFIT3的活性。 ATO 治疗抑制 UBE2O 并增加 IFIT3 表达，从而提高干扰素-α 的有效性。总之，这些研究结果表明，UBE2O 通过靶向 IFIT3 进行泛素化和降解，从而恶化干扰素-α 的治疗效果。