Charoensap, ThanchanokKilding, Andrew EBarrett, Andrew MSCross, Matt RStewart, TomMaunder, Ed2026-02-222026-02-222026-01-06Journal of Applied Physiology, ISSN: 8750-7587 (Print); 1522-1601 (Online), American Physiological Society, 140(2), 398-414. doi: 10.1152/japplphysiol.00859.20258750-75871522-1601http://hdl.handle.net/10292/20664Extracellular heat shock protein 70 (HSP70) acts as a damage-associated molecular pattern, or ‘danger signal’ for the immune system. Acute prolonged exercise evokes various physiological stresses that can stimulate the release of extracellular HSP70. However, exercise-induced extracellular HSP70 responses are inconsistent in human studies. Therefore, the purpose of this meta-analysis and meta-regression was to systematically evaluate the effect of exercise on plasma HSP70 expression, and to determine the exercise-associated factors contributing to plasma HSP70 response. Data were extracted from 26 experimental trials from thirteen studies, including 154 participants, in which plasma HSP70 was measured before and after prolonged, continuous running or cycling exercise at a fixed intensity relative to V̇O2max. Meta-analysis was performed to determine the raw mean difference (MD) between post- and pre-exercise HSP70 concentration. Meta-regression was performed to establish the moderating effects of V̇O2max, exercise intensity, duration, modality, environmental temperature, humidity, and hypoxia on the plasma HSP70 response. There was a significant effect of exercise on plasma HSP70 concentration (MD = 0.73 ng.mL−1, 95% CI [0.13, 1.34], p = 0.02). Meta-regression explained ~57.1% of variation in exercise-induced change in plasma HSP70 concentration (marginal R2 = 0.571). The V̇O2max (β = 0.51, 95% CI [0.03, 1.00]), exercise duration (β = 0.43, 95% CI [0.21, 0.65]), intensity (β = 0.40, 95% CI [0.08, 0.73]), and environmental temperature (β = 0.27, 95% CI [0.10, 0.43]) explained variation in the plasma HSP70 response. These data contribute to our understanding of the factors that modulate the plasma HSP70 response to acute prolonged exercise.Copyright © 2026 The Authors. Licensed under Creative Commons Attribution CC-BY-NC-ND 4.0. Published by the American Physiological Society.exerciseheat shock protein 70stress response32 Biomedical and Clinical Sciences42 Health Sciences4207 Sports Science and ExercisePhysical Activity06 Biological Sciences11 Medical and Health SciencesPhysiology31 Biological sciences32 Biomedical and clinical sciences42 Health sciencesHumansExerciseHSP70 Heat-Shock ProteinsOxygen ConsumptionHumansExerciseOxygen ConsumptionHSP70 Heat-Shock ProteinsHumansExerciseHSP70 Heat-Shock ProteinsOxygen ConsumptionJournal ArticleOpenAccess10.1152/japplphysiol.00859.2025