Abstract

Chronic stress has been implicated in the dysregulation of immunological, neurochemical, and endocrinological functions, yet its impact on hepatic homeostasis and liver carcinogenesis remains elusive. In this study, by using single-nucleus RNA sequencing and histopathological evaluation, we demonstrated that chronic stress induced profound hepatic dysfunction. Notably, using orthotopic murine models of liver cancer, we further found that chronic stress substantially accelerated tumor progression. Mechanistically, we identified β2-adrenergic receptor (ADRB2) signaling as the pivotal molecular pathway driving stress-accelerated cancer progression, which was in line with the poor clinical outcomes observed in patients with cancer exhibiting enhanced adrenergic signaling within tumors. Collectively, our study provides compelling evidence that chronic stress compromises hepatic homeostasis and accelerates liver cancer progression via ADRB2 activation, highlighting the therapeutic potential of targeting this pathway and the clinical importance of stress management in hepatic disorders.