Heme oxygenase/carbon monoxide in thermoregulation and neuroenergetics

This review explores the heme oxygenase/carbon monoxide (HO/CO) pathway as a central integrator of thermoregulation and neuroenergetics during inflammatory and oxidative stress. Thermoregulation is framed not merely as a homeostatic process, but as a continuous problem of energy allocation where body temperature (Tb) serves as an indicator of an organism's bioenergetic capacity. The core mechanistic thesis identifies the HO/CO system as a state-dependent "coupling pathway" that links inflammatory and redox tone to mitochondrial performance and, through central autonomic hierarchies, to the selection of thermal phenotypes, such as fever, regulated hypothermia, or torpor-like states. While fever supports "resistance" at a high metabolic cost, regulated hypothermia aligns with "tolerance" by conserving energy when resources or oxygen delivery are constrained. Key knowledge gaps remain regarding the precise cell-type-specific roles of HO-1 in the central nervous system (CNS) and the context-dependent nature of CO signaling via soluble guanylyl cyclase (sGC) in vivo. Therapeutically, targeting the HO/CO pathway via inhaled CO, CO-releasing molecules (CORMs), or HO-1 induction offers prospects for modulating neuroinflammation and metabolic resilience. However, translational constraints include timing-dependent effects and the need for precision phenotyping to identify which patients might benefit from interventions. In conclusion, the HO/CO system is discussed as a sophisticated modulator that biases thermoregulatory strategy based on the immediate physiological constraints of oxygen delivery and energetic reserve.