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Integrated single-cell transcriptomics and proteomics elucidate the molecular mechanisms and detoxification strategy of rifampicin-induced hepatotoxicity

Year: 2025

Type: article

Abstract: Rifampicin (RIF), a cornerstone drug in tuberculosis treatment, is associated with hepatotoxicity, which represents a significant adverse effect that frequently causes discontinuation of therapy.However, a comprehensive evaluation of the mechanisms underlying RIF-induced hepatotoxicity remains limited, and the identification of highly effective, low-toxicity therapeutic interventions is urgently needed.In this study, we employed a RIF-induced mouse hepatotoxicity model to systematically investigate the cellular and molecular events associated with RIF-induced liver injury.By integrating single-cell RNA sequencing, bulk RNA-seq, and mass spectrometry-based proteomics and metabolomics, we identified region-specific hepatocyte damage characterized by elevated reactive oxygen species (ROS) levels and activation of the fatty acid oxidation pathway.At the molecular level, RIF treatment resulted in the upregulation of pregnane X receptor (PXR) and Cyp3a11, along with the downregulation of key antioxidant genes.Moreover, decreased mTOR expression and increased expression of fatty acid oxidation-related genes including Acox1 and Acaa1b suggested an enhanced oxidative metabolism.Recruitment of macrophages further exacerbated hepatocyte damage.Importantly, Rosmarinic acid (RA) administration was shown to attenuate RIF-induced hepatotoxicity.These findings provide a comprehensive molecular and cellular perspective on RIF-induced hepatotoxicity and suggest the potential clinical application of RA as a therapeutic agent in the management of RIF-induced liver injury.

Source: International Journal of Biological Sciences

DOI: 10.7150/ijbs.109757