Ebert, T.

Acute stress triggers rapid physiological adaptations, yet how distinct stress modalities shape the human circulating molecular landscape remains unclear. We performed longitudinal deep plasma proteomics and targeted metabolomics across three paradigms: psychological stress, controlled physical stress, and combined psychological-physical stress induced by bungee jumping. Despite robust hypothalamic-pituitary-adrenal axis activation, psychological stress induced minimal plasma proteomic and metabolic changes, whereas physical stress triggered rapid, coordinated proteome remodeling accompanied by stressor-specific metabolic adaptations. Combined stress elicited the strongest and most persistent proteomic response, defining a graded molecular signature across stress modalities. Cross-paradigm integration identified a stress-associated protein core enriched for immune granule effectors, RNA-binding proteins, and vesicle-linked signatures, suggesting regulated extracellular release. Consistently, extracellular vesicle profiling in the mixed-stress paradigm supported vesicle-associated secretion, while functional experiments indicated that glucocorticoid signaling alone is insufficient to trigger release. Together, these findings reveal stressor identity as a key determinant of the human circulating molecular response.