FOXO transcription factors as therapeutic targets in human diseases

Alba Orea-Soufi; Jihye Paik; José Bragança; Timothy A Donlon; Bradley J Willcox; Wolfgang Link

doi:10.1016/j.tips.2022.09.010

FOXO transcription factors as therapeutic targets in human diseases

Trends Pharmacol Sci. 2022 Dec;43(12):1070-1084. doi: 10.1016/j.tips.2022.09.010. Epub 2022 Oct 21.

Authors

Alba Orea-Soufi¹, Jihye Paik², José Bragança³, Timothy A Donlon⁴, Bradley J Willcox⁵, Wolfgang Link⁶

Affiliations

¹ 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.
² Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
³ 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; Champalimaud Research Program, Champalimaud Center for the Unknown, Lisbon, Portugal.
⁴ Department of Research, Kuakini Medical Center, Honolulu, HI 96817, USA; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA.
⁵ Department of Research, Kuakini Medical Center, Honolulu, HI 96817, USA; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA.
⁶ Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Arturo Duperier 4, 28029-Madrid, Spain. Electronic address: walink@iib.uam.es.

PMID: 36280450
DOI: 10.1016/j.tips.2022.09.010

Abstract

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.

Keywords: FOXO transcription factors; aging; cancer; cardiovascular and neurodegenerative diseases; diabetes; drugs and geroprotectors.

Publication types

Review
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Forkhead Transcription Factors* / genetics
Forkhead Transcription Factors* / metabolism
Humans
Longevity*

Substances

Forkhead Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding