By Heba Ibrahim Abd El-Moaty, Sameh Saber, Fatma Elnaghy,…., Simona Cavalu et al.

Highlights

• FOXO3a orchestrates structural remodeling of liver cells via stress-responsive transcriptional programs.
• Dual FOXO3a actions modulate hepatocyte apoptosis and survival through Bim, PUMA, and antioxidant genes.
• Post-translational FOXO3a regulation reshapes nuclear–cytoplasmic dynamics impacting tissue homeostasis.
• FOXO3a-controlled autophagy and mitophagy pathways preserve hepatocyte integrity under cellular stress.
• Crosstalk between FOXO3a and liver-specific signaling networks defines context-dependent tissue outcomes. By Heba Ibrahim Abd El-Moaty, Sameh Saber,…., Simona Cavalu et al.

FOXO3a, a member of the forkhead box O transcription factor family, has emerged as a pivotal regulator of cellular fate in liver physiology and pathology. Its activity integrates multiple stress signals to orchestrate antioxidant defense, autophagy, and apoptosis, placing it at the intersection of survival and death pathways. Notably, FOXO3a demonstrates a dual role in apoptosis: under certain contexts, it promotes hepatocyte death through activation of pro-apoptotic genes such as Bim and PUMA, contributing to disease progression; conversely, it mitigates oxidative stress and supports cell survival by inducing antioxidant enzymes and autophagy-related genes. This paradox emphasizes FOXO3a as both a mediator of injury and a guardian of homeostasis, based on cellular and environmental cues. In liver disorders, FOXO3a influences critical processes including oxidative injury, inflammation, fibrosis, ischemia/reperfusion responses, and regeneration. Its modulation of mitochondrial function and autophagic flux underscores its importance in maintaining hepatocyte integrity, while its context-dependent activation can either exacerbate damage or promote recovery. These multifaceted actions make FOXO3a an attractive therapeutic target, with potential strategies aimed at fine-tuning its action to restore balance between apoptosis and survival. Enhancing FOXO3a function may support regeneration and protect against acute stress, whereas its inhibition may prevent excessive cell death and limit fibrosis. Overall, FOXO3a functions as a molecular switch in liver disease pathogenesis, and precision targeting of its signaling pathways holds promise for innovative interventions that maintain tissue homeostasis while preventing progression of chronic injury. By Heba Ibrahim Abd El-Moaty, Sameh Saber,…., Simona Cavalu et al.

Full text at https://doi.org/10.1016/j.tice.2026.103375