Environmental heat exposure triggers neuronal apoptosis via NCOA4-mediated ferritinophagy.

Global warming increases the frequency and intensity of environmental heat exposure, posing a growing threat to public health. While heat-related mortality is well-documented, the neurological consequences of heat exposure remain poorly characterized at the mechanistic level. Here, by integrating epidemiological data from the US National Health and Nutrition Examination Survey (NHANES), clinical transcriptomic data from heatstroke patients, and experimental models, we identified intracellular iron dyshomeostasis as a critical driver of heat-induced neuronal injury. Mechanistically, severe heat exposure activates the extracellular signal-regulated kinase pathway, which stabilizes nuclear receptor coactivator 4 by suppressing its ubiquitination. The subsequent accumulation of Nuclear receptor coactivator 4 (NCOA4) recruits microtubule-associated protein 1 light chain 3B (LC3B) to drive excessive ferritin degradation via ferritinophagy. This process expands the labile iron pool (LIP) and triggers reactive oxygen species (ROS) production, which primarily executes neuronal apoptosis. Notably, pharmacological intervention with the iron chelator deferasirox (DFX) effectively alleviated heat-induced neurological damage by disrupting this iron-dependent cascade. Our findings establish the ERK/NCOA4/LC3B-mediated ferritinophagy pathway as a promising therapeutic target, providing a translational foundation for interventions against heat-induced neurological injuries.