正确识别受到干扰的生物途径是揭示基本疾病机制和制定急需的治疗策略的关键一步。然而，目前的工具是否最适合公正地发现相关途径仍不清楚。在这里，我们创建“基准”来严格评估现有工具，并发现大多数工具的功能都不是最佳的。因此，我们开发了“Pathway Ensemble Tool”（PET），其性能优于现有方法。利用 PET，我们确定了 12 种癌症类型的预后途径。 PET 识别的预后途径提供了额外的见解，这些途径中的基因可作为临床结果的可靠生物标志物。此外，使用药物再利用策略使这些途径正常化代表了治疗机会。例如，最受预测的膀胱癌再利用药物是一种 CDK2/9 抑制剂，可在体外和体内抑制细胞生长。我们预计，使用 Benchmark 和 PET 进行公正的通路发现将为了解一系列疾病的疾病机制提供更多见解，从而实现生物标志物发现和治疗策略。© 2024。作者。

Correctly identifying perturbed biological pathways is a critical step in uncovering basic disease mechanisms and developing much-needed therapeutic strategies. However, whether current tools are optimal for unbiased discovery of relevant pathways remains unclear. Here, we create "Benchmark" to critically evaluate existing tools and find that most function sub-optimally. We thus develop the "Pathway Ensemble Tool" (PET), which outperforms existing methods. Deploying PET, we identify prognostic pathways across 12 cancer types. PET-identified prognostic pathways offer additional insights, with genes within these pathways serving as reliable biomarkers for clinical outcomes. Additionally, normalizing these pathways using drug repurposing strategies represents therapeutic opportunities. For example, the top predicted repurposed drug for bladder cancer, a CDK2/9 inhibitor, represses cell growth in vitro and in vivo. We anticipate that using Benchmark and PET for unbiased pathway discovery will offer additional insights into disease mechanisms across a spectrum of diseases, enabling biomarker discovery and therapeutic strategies.© 2024. The Author(s).