biostudies-literatureZhang JNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)44https://www.ebi.ac.uk/biostudies/studies/S-EPMC7925512biostudies-literatureUnknown7(1)Ischemia-reperfusion (IR) injury to the renal epithelia is associated with endoplasmic reticulum stress (ERS) and mitochondria dysfunction, which lead to oxidative stress-induced acute kidney injury (AKI). X-box binding protein 1 (XBP1), an ERS response protein, could play a prominent role in IR-induced AKI. In this study, we revealed that XBP1 and its downstream target HRD1 participated in the crosstalk between ERS and mitochondrial dysfunction via regulation of NRF2/HO-1-mediated reactive oxidative stress (ROS) signaling. Mice with reduced expression of XBP1 (heterozygous Xbp1±) were resistant to IR-induced AKI due to the enhanced expression of NRF2/HO-1 and diminished ROS in the kidney. Downregulation of XBP1 in renal epithelial cells resulted in reduced HRD1 expression and increased NRCell death discoveryDownregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation.PMC7925512815706788150057381873623Wang MZhang JNi HChen GGong NMiao YKatwal GLi QWang YZhao YSun KfalseDownregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation.Ischemia-reperfusion (IR) injury to the renal epithelia is associated with endoplasmic reticulum stress (ERS) and mitochondria dysfunction, which lead to oxidative stress-induced acute kidney injury (AKI). X-box binding protein 1 (XBP1), an ERS response protein, could play a prominent role in IR-induced AKI. In this study, we revealed that XBP1 and its downstream target HRD1 participated in the crosstalk between ERS and mitochondrial dysfunction via regulation of NRF2/HO-1-mediated reactive oxidative stress (ROS) signaling. Mice with reduced expression of XBP1 (heterozygous Xbp1±) were resistant to IR-induced AKI due to the enhanced expression of NRF2/HO-1 and diminished ROS in the kidney. Downregulation of XBP1 in renal epithelial cells resulted in reduced HRD1 expression and increased NR2021-01-01T00:00:00Z2021 Mar2026-07-14T14:39:24.394Z2025-04-21T17:06:57.041ZS-EPMC79255123365407210.1038/s41420-021-00425-z