Integrative metabolomics and proteomics analyses reveal the mechanism underlying neurotoxicity of rifampicin in HT22 cells

Rifampicin is orally administered in the treatment of tuberculosis but is sometimes accompanied with neurotoxicity. The mechanism behind rifampicin-induced neurotoxicity remains unclear and need to be further researched. To systematically explore this mechanism, integrative metabolomic and proteomic analyses were performed to investigate rifampicin-induced injury in HT22 cells. HT22 cells were treated with rifampicin at concentrations ranging from 0 to 400 μg/mL, and cell viability and apoptosis were assessed. Subsequently, cells treated with 0 μg/mL and 200 μg/mL rifampicin were collected for mass spectrometry-based proteomic and metabolomic analyses, serving as the control group and the rifampicin model group, respectively. Viability and apoptosis data revealed dose-dependent injury after exposure to rifampicin, with 200 μg/mL identified as a suitable dose for proteomic and metabolomic studies. In total, 253 proteins and 28 metabolites were shown to be dysregulated. In addition, our integrated multi-omics analysis highlighted the glutathione metabolism pathway as a central disrupted pathway in HT22 cells, leading to rifampicin-induced neurotoxicity. Therefore, more efforts should be paid to explore the mechanism of glutathione metabolism, and it may be a key therapeutic target for alleviating rifampicin - induced neurotoxicity.