Systemic stress states are reversed by NPBWR1 inhibition

Abstract

Chronic stress is widely studied as a brain-centered driver of depression, yet its effects across the body remain unclear. Here, we define chronic stress as a coordinated molecular state across tissues in mice. Using a whole-body proteomic atlas of 13 tissues, we find that stress effects are strongest in peripheral metabolic and endocrine organs, whereas classical stress-associated brain regions show comparatively modest changes. Cross-organ analyses reveal structured, tissue-specific responses rather than uniform shifts. Inhibition of the stress-regulated receptor NPBWR1 reverses both behavioral deficits and proteomic alterations across organs in both sexes, indicating that this state is dynamically modifiable. Integration with human serum proteomics identifies shared, sex-specific signatures. Across tissues, lipid metabolism emerges as a common stress-responsive pathway, confirmed by hepatic lipid remodeling that is normalized by NPBWR1 inhibition. To facilitate exploration of these data, we provide an interactive cross-organ web-based resource. Together, these findings challenge the brain-centric view of stress pathology and define chronic stress as an organism-wide molecular state.