ZBP1 Promotes RIPK1-Dependent Apoptosis in Aristolochic Acid Nephropathy
Zhenhuan Zou1, Keng Ye1, Fengbin Chen1
1Chazhong road 20 Fuzhou Fuzhou China 350005.
Zoological Research
|March 1, 2026
Summary
Aristolochic acid causes kidney injury via Z-DNA-binding protein 1 (ZBP1) and RIPK1-dependent apoptosis. Blocking this ZBP1-RIPK1 pathway may treat aristolochic acid nephropathy.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Aristolochic acid nephropathy (AAN) is a severe kidney disease linked to traditional medicines.
- Mitochondrial apoptosis is key in AAN, but upstream triggers are unknown.
Purpose of the Study:
- Identify upstream mediators of aristolochic acid-induced kidney injury.
- Investigate the role of Z-DNA-binding protein 1 (ZBP1) in AAN pathogenesis.
Main Methods:
- Utilized Zbp1 knockout and Zα domain-mutant mice models.
- Analyzed renal dysfunction, apoptosis, and inflammation markers.
- Investigated molecular signaling pathways involving ZBP1, RIPK1, and caspases.
Main Results:
- ZBP1 deficiency protected against AA-induced kidney injury, apoptosis, and inflammation.
- AA triggers mitochondrial damage, releasing Z-form mtDNA recognized by ZBP1.
- ZBP1 activates RIPK1, leading to caspase-8-mediated apoptosis, independent of RIPK3/MLKL.
Conclusions:
- A novel ZBP1-RIPK1-caspase-8 axis drives non-canonical apoptosis in AAN.
- Targeting this pathway offers a potential therapeutic strategy for nephrotoxin-induced kidney injury.
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