Gene expression identifies regional central nervous system vulnerability to heat

Heat-related illness is an increasing global health threat, with heatstroke representing its most severe form and frequently causing cerebellar injury characterised by selective Purkinje neuron loss. The molecular basis of this regional vulnerability remains unclear. Here, we integrated transcriptomic data from human heat exposure experiments, patients with heatstroke, primary human neurons, and cortical organoids to define conserved responses to heat stress and investigate determinants of cerebellar susceptibility. Across datasets, heat stress induced a highly conserved transcriptional programme dominated by suppression of ribosome biogenesis, RNA processing, translation, and metabolic pathways, consistent with reduced biosynthetic and energy-demanding activity. Mapping these signatures to human brain atlases revealed that the cerebellum showed the lowest enrichment of downregulated genes, while heatstroke exhibited a distinct regional transcriptional pattern compared with experimental heat exposure. At the cellular level, granule and Purkinje neurons showed the strongest association with heat-responsive gene suppression. Purkinje-enriched genes were linked to synaptic organisation, neurotransmission, membrane excitability, and ion transport. Connectivity Map analysis identified compounds predicted to reverse the heatstroke transcriptional signature, including the mTOR inhibitor KU-0063794. These findings identify a conserved molecular response to heat stress and suggest that selective Purkinje vulnerability reflects intrinsic metabolic and electrophysiological properties rather than preferential activation of canonical heat-shock pathways.