Targeting FOXO3 for the Management of Heart Failure: Current Evidence and Future Directions

Heart failure (HF) is a multifaceted clinical syndrome marked by the heart’s inability to pump sufficient blood, resulting in symptoms such as dyspnea, fatigue, and fluid retention. Among the emerging therapeutic strategies for managing HF, targeting the transcription factor forkhead box O3 (FOXO3) has garnered attention due to its regulatory role in cellular processes related to oxidative stress, apoptosis, autophagy, and inflammation. Dysregulation of FOXO3 has been implicated in the progression of HF, making it a notable focus for potential therapeutic interventions aimed at improving cardiac function and patient outcomes. Research into FOXO3-targeting compounds has identified various classes of agents, including phytochemicals and pharmaceuticals. These compounds work through mechanisms such as interaction with upstream signaling pathways and downstream target genes of FOXO3. While preclinical studies show promise for FOXO3 targeting compounds in promoting cardiac health and function, challenges remain in translating these findings into successful clinical applications. In this review article, we focus on the FOXO3 modulators investigated between 2006 and 2026 that have shown beneficial effects on heart function in diverse experimental models. Furthermore, we discuss current methodological limitations in this research field and propose potential directions for future studies on heart health management.