GPD1-mediated neuronal lipotoxicity drives aconitine-induced mitochondrial collapse and lethality.

Aconitine (AC) ranks among the leading causes of fatal herbal poisoning globally due to its narrow therapeutic window. Although its cardiovascular toxicity has been extensively studied, the precise molecular mechanisms underlying AC-induced central nervous system damage remain unclear. This study aimed to investigate the role of glycerol-3-phosphate dehydrogenase 1 (GPD1) in AC-induced neurotoxicity and to elucidate the underlying metabolic and molecular mechanisms. In a rat model of acute AC poisoning, significant neurological impairments, anxiety-like behaviors, and neuron-specific cell death were observed. Transcriptomic analyses revealed marked metabolic reprogramming following AC exposure, characterized by upregulation of GPD1 and suppression of the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. Mechanistically, AC disrupted GPD1/PPARγ signaling homeostasis, leading to pathological lipid droplet accumulation and mitochondrial dysfunction, as evidenced by loss of membrane potential and ATP depletion, ultimately resulting in neuronal apoptosis. Notably, targeted knockdown of Gpd1 using shRNA alleviated lipid accumulation, restored mitochondrial function, and significantly improved survival rates and neurological outcomes in poisoned rats. These findings identify the aconitine-GPD1-lipid/mitochondrial axis as a key mechanism underlying AC-induced neurotoxicity and suggest GPD1 as a potential therapeutic target.