Prolonged Humid Heat Triggers Systemic Inflammation and Stress Signaling: Fluid Intake Modulates NF-κB, p38, JNK2, and STAT3α Pathways

Prolonged exposure to extreme humid heat can induce systemic inflammation, organ stress, and hormonal imbalance. While fluid replacement is commonly recommended, its mechanistic efficacy under humid heat stress remains unclear. This study investigated the impact of fluid intake on thermoregulation, inflammation, organ function, and stress signaling during 8 h of humid heat exposure (ambient temperature: 40 °C, relative humidity: 55%) in 32 healthy young adults (20 males and 12 females). Participants completed two randomized trials: limited fluid intake (LFI, 125 mL/h) and full fluid intake (FFI, 375 mL/h). Core temperature (<i>T_core</i>), inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α), organ stress markers (ALT, BUN), oxidative stress indices (MDA, SOD), and cortisol were assessed pre- and post-exposure. FFI significantly reduced post-exposure <i>T_core</i> (37.8 ± 0.3 °C vs. 38.1 ± 0.3 °C, <i>p</i> = 0.046), mitigated cytokine elevations, and decreased BUN (blood urea nitrogen), ALT (alanine aminotransferase), and cortisol levels. Western blot analysis of PBMCs revealed that LFI activated NF-κB p65, JNK2, p38, and STAT3α phosphorylation, whereas FFI suppressed these responses. These findings demonstrate that adequate hydration attenuates heat-induced systemic and molecular stress responses. Our results highlight hydration as a key modulator of inflammatory signaling pathways during prolonged heat stress, offering insights into preventive strategies for populations vulnerable to climate-induced extreme heat events.