Chronic psychological stress disrupts liver homeostasis by dysregulating oxidative phosphorylation via the...

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.