Discovery of triphenylphosphonium (TPP+)-conjugated GNX-865 and therapeutic hypothermia in neuron acute ischemia-reperfusion injury: the RISK pathway and mitochondrial permeability transition pore opening.

Hypoxic-ischemic brain damage (HIBD) poses a significant challenge to healthcare systems and severely impacts patients' quality of life. Therapeutic hypothermia is the most effective and widely recommended treatment; however, its molecular mechanism remains unclear. In this study, the meta-transcriptome analysis identified the mitochondrial permeability transition pore (MPTP) as a key pathway involved in HIBD. We demonstrated that the activation of the reperfusion injury salvage kinase (RISK) pathway and subsequent inhibition of MPTP opening underlie the neuroprotective effects of therapeutic hypothermia. To further explore therapeutic strategies, we synthesized TPP+-GNX-865, a mitochondrial-targeting derivative of the MPTP opening inhibitor GNX-865, and investigated its potential application in HIBD treatment. Our findings provide novel insights into the mechanisms of therapeutic hypothermia and introduce a promising therapeutic agent for HIBD.