Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal; Faculty of Medicine and Biomedical Sciences, Campus de Gambelas, 8005-139 Faro, Portugal.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Trends Pharmacol Sci. 2022 Dec;43(12):1070-1084. doi: 10.1016/j.tips.2022.09.010. Epub 2022 Oct 21.
Forkhead box (FOX)O proteins are transcription factors (TFs) with four members in mammals designated FOXO1, FOXO3, FOXO4, and FOXO6. FOXO TFs play a pivotal role in the cellular adaptation to diverse stress conditions. FOXO proteins act as context-dependent tumor suppressors and their dysregulation has been implicated in several age-related diseases. FOXO3 has been established as a major gene for human longevity. Accordingly, FOXO proteins have emerged as potential targets for the therapeutic development of drugs and geroprotectors. In this review, we provide an overview of the most recent advances in our understanding of FOXO regulation and function in various pathological conditions. We discuss strategies targeting FOXOs directly or by the modulation of upstream regulators, shedding light on the most promising intervention points. We also reveal the most relevant clinical indications and discuss the potential, trends, and challenges of modulating FOXO activity for therapeutic purposes.
叉头框 (FOX)O 蛋白是具有四个成员的转录因子 (TFs)，在哺乳动物中分别命名为 FOXO1、FOXO3、FOXO4 和 FOXO6。FOXO TFs 在细胞适应各种应激条件中起着关键作用。FOXO 蛋白作为上下文相关的肿瘤抑制因子发挥作用，其失调与几种与年龄相关的疾病有关。FOXO3 已被确立为人类长寿的主要基因。因此，FOXO 蛋白已成为药物和抗衰老保护剂治疗开发的潜在靶点。在这篇综述中，我们提供了对 FOXO 在各种病理条件下的调节和功能的最新理解的概述。我们讨论了直接针对 FOXO 或通过调节上游调节剂的策略，阐明了最有前途的干预点。我们还揭示了最相关的临床适应症，并讨论了调节 FOXO 活性用于治疗目的的潜力、趋势和挑战。
