Thermoregulatory limits in an era of climate change: A systematic review of molecular insights

Climate change is increasing the frequency and intensity of heat exposure, elevating risks of heat-related morbidity and mortality. At the cellular level, heat shock proteins (HSPs), particularly HSP70 and HSP90, mediate proteostasis and may indicate thermotolerance.

To systematically review and quantitatively synthesize evidence on intracellular HSP70 and HSP90 responses to controlled heat exposure in humans and other mammals.

Following PRISMA 2020, we searched PubMed, Web of Science, Scopus, and Google Scholar to 30 May 2025. Eligible studies involved healthy mammals or humans exposed to controlled heat, with a thermoneutral comparator and quantitative intracellular HSP70/HSP90 outcomes.

Of 630 records, 35 studies met the criteria. Across studies, intracellular HSP70 rose robustly after single heat bouts and with multi-day heat acclimation; acclimation elevated baseline HSP70 and blunted further inducibility to a fixed heat stimulus (consistent with cellular preconditioning). HSP90 responses were smaller and less consistent. A meta-analysis of four human studies (n = 33) showed a large increase in basal intracellular HSP70 after acclimation (pooled g = 0.92, 95 % CI 0.31-1.53; I² ~ 57 %). Risk of bias was generally low to some concerns.

Intracellular HSP70 shows a consistent, large heat-responsive signal and appears to index acquired thermotolerance, supporting its use as a primary molecular marker of heat adaptation. HSP90 contributes but is less uniformly inducible. While HSP70 alone may not capture all facets of heat resilience, these findings support heat-acclimation strategies and motivate further work on durability of HSP elevations, moderator effects (species, tissue, protocol), and multi-marker panels.