Lactate reprogramming hijacks BDNF neuroprotection to drive hippocampal injury after CO poisoning

Carbon monoxide (CO) poisoning is a leading cause of neurological injury, yet the underlying metabolic-neurotrophic mechanisms remain unclear. Through pre-clinical experiments, we integrated glycolytic metabolomics with single-cell RNA sequencing(scRNA-seq) of the rat hippocampus and identified specific metabolic reprogramming processes in exNeuGRIK3 excitatory neurons, characterized by up-regulation of lactate dehydrogenase A (LDHA) and lactate accumulation for ischemia-hypoxia and mitochondrial complex IV inhibition. Meanwhile, the disrupted Grn-Sortilin signaling between neurons and microglia was also detected. We also observed elevated serum lactate levels in patients with acute CO poisoning. Mechanically, CO-induced lactate accumulation might trigger lysosomal overactivation, leading to Sortilin degradation, impaired Grn trafficking, and subsequent brain-derived neurotrophic factor (BDNF) maturation, which ultimately driven neuronal apoptosis. In vitro experiments showed that exogenous lactate or knockdown of Sortilin or Grn exacerbated apoptosis, whereas inhibition of lysosomal function using bafilomycin A1, or knockdown of LDHA could restore Sortilin and BDNF levels and mitigate apoptosis. Collectively, CO poisoning activates the LDHA-lactate-lysosome axis and degrades Sortilin, disrupts neuron-microglia communication and BDNF maturation, and ultimately drives neuronal apoptosis. Targeting this metabolic-neurotrophic axis might offer a novel therapeutic strategy for acute CO poisoning.