XBP1 activation elevates abnormal synthesis of polyunsaturated fatty acids in hepatocytes to promote liver injury during anti-tuberculosis drug metabolism

Objective This study aimed to explore new mechanistic insight into the link between abnormal lipid metabolism and ATB-DILI. Methods We performed integrative analyses of RNA-Seq, ChIP-Seq, lipids mass spectrometry, in vivo and in vitro experiments, and clinical samples to identify the key pathways and molecules involved in the process of ATB-DILI. Results Our study revealed that the cellular polyunsaturated fatty acids (PUFAs) synthesis was abnormally activated in hepatocytes during anti-TB drug metabolism. The levels of phosphatidylethanolamine substrates, ferroptosis-related arachidonic acid, and key enzyme Acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly up-regulated in ATB-DILI. Further exploration indicated that this phenomenon was linked to the endoplasmic reticulum stress factor X-box binding protein 1 (XBP1). XBP1 activation significantly enhanced the synthesis of PUFAs, thereby increasing the level of lipid peroxidation and ferroptosis, ultimately resulting in ATB-DILI. Moreover, serum Apolipoprotein levels in A-IV (APOA4) and triglyceride were elevated and may serve as early warning biomarkers for ATB-DILI. Conclusions These results systematically revealed the importance of XBP1 as a therapeutic target, and clarified the feasibility of using APOA4 and triglyceride as novel early warning biomarkers for ATB-DILI.