Chronic psychological stress disrupts liver homeostasis by dysregulating oxidative phosphorylation via the PI3K/AKT/FoxO3a axis.

Epidemiological evidence indicates that chronic psychological stress correlates with the morbidity and mortality of chronic liver disease. However, the underlying mechanisms remain unclear. We established a chronic restraint stress (CRS) mouse model to simulate emotional stress. Histological and biochemical analyses showed marked hepatocyte vacuolization, increased transaminase levels, and apoptosis, signifying injury. Single-cell RNA sequencing showed that psychological stress suppresses oxidative phosphorylation (OXPHOS), consistent with mitochondrial abnormalities identified by electron microscopy. Forkhead box O (FoxO)3a was identified as a key transcription factor mediating CRS-induced OXPHOS inhibition, particularly in periportal hepatocytes (zone 1). Furthermore, FoxO3a-driven epigenetic silencing contributed to OXPHOS reduction. In upstream signaling, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was suppressed, leading to enhanced FoxO3a activity. Collectively, these findings reveal that chronic stress disrupts hepatocyte homeostasis via PI3K/AKT/FoxO3a-mediated OXPHOS dysregulation. This study deepens the understanding of psychological stress-induced liver dysfunction and highlights impaired mitochondrial oxidative metabolism as a potential therapeutic target for psychological intervention in liver disorders.