ZBP1 promotes RIPK1-dependent apoptosis in aristolochic acid nephropathyOA
Aristolochic acid nephropathy(AAN)is a progressive kidney disease marked by acute tubular injury and interstitial fibrosis that frequently advances to end-stage renal disease(ESRD).Despite regulatory restrictions,aristolochic acid(AA)continues to pose a global health risk due to persistent exposure through traditional herbal medicines.Although mitochondria-mediated apoptosis is a defining hallmark of AA-induced tubular epithelial cell(TEC)injury,the upstream molecular mechanisms remain poorly resolved.The present study identified Z-DNAbinding protein 1(ZBP1)as a key mediator of AAI-induced kidney injury.Using Zbp1 knockout(Zbp1−/−)and Zαdomain-mutant(ZαMut)mice,loss of ZBP1 or disruption of Z-form nucleic acid sensing conferred marked protection against AAI-induced renal dysfunction,apoptosis,and inflammation.Mechanistic analyses showed that aristolochic acid I(AAI)triggered mitochondrial oxidative stress and promoted mitochondrial DNA(mtDNA)release,after which mtDNA adopted a Z-conformation recognized by ZBP1.ZBP1 engagement then promoted RHIMdependent association with RIPK1,leading to caspase-8 activation and apoptotic cell death.Notably,ZBP1-mediated cell death was abolished by RIPK1 kinase inhibition or mutation but remained unchanged after Ripk3 or Mlkl deletion,indicating a pathway distinct from RIPK3/MLKL-dependent necroptosis.These findings define a previously unrecognized ZBP1-RIPK1-caspase-8 signaling axis that drives non-canonical apoptosis in AAN and identify this pathway as a potential therapeutic target in nephrotoxin-induced kidney injury.
Zhenhuan Zou;Keng Ye;Fengbin Chen;Kongwen Lin;Yankun Song;Guoping Li;Caiming Chen;Yujia Wang;Huabin Ma;Yanfang Xu
Department of Nephrology,Blood Purification Research Center,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Research Center for Metabolic Chronic Kidney Disease,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Department of Nephrology,National Regional Medical Center,Binhai Campus of the First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350212,ChinaDepartment of Nephrology,Blood Purification Research Center,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Research Center for Metabolic Chronic Kidney Disease,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Department of Nephrology,National Regional Medical Center,Binhai Campus of the First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350212,ChinaDepartment of Traditional Chinese Medicine,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,ChinaDepartment of Nephrology,Blood Purification Research Center,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Research Center for Metabolic Chronic Kidney Disease,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Department of Nephrology,National Regional Medical Center,Binhai Campus of the First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350212,ChinaDepartment of Pathology,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,ChinaDepartment of Pathology,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,ChinaDepartment of Nephrology,Blood Purification Research Center,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Research Center for Metabolic Chronic Kidney Disease,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Department of Nephrology,National Regional Medical Center,Binhai Campus of the First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350212,ChinaDepartment of Nephrology,Blood Purification Research Center,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Research Center for Metabolic Chronic Kidney Disease,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Department of Nephrology,National Regional Medical Center,Binhai Campus of the First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350212,ChinaResearch Center for Metabolic Chronic Kidney Disease,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Central Laboratory,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,ChinaDepartment of Nephrology,Blood Purification Research Center,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Research Center for Metabolic Chronic Kidney Disease,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China Department of Nephrology,National Regional Medical Center,Binhai Campus of the First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350212,China Central Laboratory,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China
医药卫生
Aristolochic acid nephropathyApoptosisMitochondriaZBP1Z-DNA
《Zoological Research》 2026 (2)
P.577-592,16
supported by the National Natural Science Foundation of China(U23A20410,82470710)Young and Middle-aged Scientific Research Major Project of Fujian Provincial Health Commission(2021ZQNZD004)Program of the First Affiliated Hospital of Fujian Medical University(YJRC4104)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare(2022ZQNRCYX-XYF)。
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