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00925njm 22002777a 4500 dc Ye, Hui author Chen, Chaobo author Wu, Hanghang author Zheng, Kang author Martín-Adrados, Beatriz author Caparrós, Esther author Francés, Rubén author Nelson, Leonard J author Gómez Del Moral, Manuel author Asensio, Iris author Vaquero, Javier author Bañares, Rafael author Ávila, Matías A author Andrade, Raúl J author Isabel Lucena, M author Martínez-Chantar, Maria Luz author Reeves, Helen L author Masson, Steven author Blumberg, Richard S author Gracia-Sancho, Jordi author Nevzorova, Yulia A author Martínez-Naves, Eduardo author Cubero, Francisco Javier author 2022-02-10 Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury. 10.1038/s41419-022-04580-8 2041-4889 Cell death & disease http://hdl.handle.net/10668/19527 35145060 http://hdl.handle.net/20.500.12105/18603 Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.