RT Journal Article T1 Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy A1 Hui, Ye A1 Chaobo, Chen A1 Hanghang, Wu A1 Kang, Zheng A1 Martín Adrados, Beatriz A1 Caparros, Esther A1 Francés, Rubén A1 Nelson, Leonard J. A1 Gómez Del Moral Martín-Consuegra, Manuel María A1 Asensio, Iris A1 Javier Vaquero, A1 Bañares Cañizares, Rafael A1 Ávila, Matías A. A1 Andrade, Raúl J. A1 Lucena, María Isabel A1 Martínez Chantar, Maria Luz A1 Reeves, Helen L. A1 Masson, Steven A1 Blumberg, Richard S. A1 Gracia Sancho, Jordi A1 Nevzorova, Yulia A1 Martínez Naves, Eduardo A1 Cubero Palero, Francisco Javier AB 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. PB Springer Nature SN 2041-4889 YR 2022 FD 2022-02-10 LK https://hdl.handle.net/20.500.14352/92253 UL https://hdl.handle.net/20.500.14352/92253 LA eng NO e, H., Chen, C., Wu, H. et al. Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy. Cell Death Dis 13, 143 (2022). https://doi.org/10.1038/s41419-022-04580-8 NO Ministerio de Economía, Comercio y Empresa NO German Research Foundation DS Docta Complutense RD 30 sept 2024