Preoptic activation induces a torpor-like hypothermic and hypometabolic state that is cerebroprotective.

Therapeutic hypothermia for stroke has been limited by shivering, increased metabolic demand, and poor patient tolerance. Engaging endogenous thermoregulatory circuits to lower body temperature may overcome these limitations and modulate metabolism, offering an integrated approach to cerebroprotection. Here, we show that chemogenetic activation of neurons in the preoptic area (POA) elicits a torpor-like state in mice, characterized by sustained hypothermia and hypometabolism. In an animal stroke model, this endogenous hypothermic state significantly reduced infarct volume and improved motor outcomes compared to controls, whereas maintaining normothermia attenuated these protective effects. To explore metabolic mechanisms contributing to this state, we performed untargeted metabolomic profiling 30 minutes after POA activation and identified coordinated shifts in nucleotide, phospholipid, and sphingolipid pathways. These rapid, temperature-dependent changes indicate a metabolically reprogrammed state that may enhance neuronal resilience during ischemic stress. Together, our findings suggest that POA-driven hypothermia confers cerebroprotection through specific metabolic adaptations with translational potential.