High-density lipoprotein cholesterol protects against delayed encephalopathy after acute carbon monoxide poisoning

High-density lipoprotein cholesterol (HDL-C) plays a crucial role in neurological disorders. In this study, we aimed to elucidate the role of HDL-C in delayed encephalopathy after acute carbon monoxide poisoning (DEACMP), which presents with both neurological and psychiatric symptoms. Two-sample Mendelian randomization was employed on 201 lipid summary statistics to investigate potential causality. Data from the FinnGen database of 306,787 individuals were used. Mendelian randomization analysis results were screened using Bayesian model averaging. The results were validated in a multicenter cohort of 1368 patients, and the role of the antioxidant properties of high-density lipoprotein in DEACMP was examined. Mendelian randomization analysis identified six high-density lipoprotein-related variants significantly associated with DEACMP, with the cholesterol to total lipids ratio in medium high-density lipoprotein showing the strongest effect (marginal inclusion probability = 0.51, p = 1.00 × 10^-3, false discovery rate = 6.00 × 10^-3). Clinical validation confirmed HDL-C as an independent protective factor. Patients without DEACMP had higher high-density lipoprotein oxidant index values (1.23 [interquartile range: 1.02-1.36]) than those who developed DEACMP (0.84 [interquartile range: 0.66-0.90]); the high-density lipoprotein oxidant index declined significantly in postmenopausal women (p = 0.023). These findings demonstrate that HDL-C mitigates the risk of DEACMP through its antioxidant capacity. The integration of genetic evidence, clinical validation, and functional assays provides robust support for HDL-C as a predictive biomarker of neural recovery after carbon monoxide poisoning.