Abstract: TH-PO0680
ANXA3 Mediates Pyroptosis of Renal Tubular Epithelial Cells in Septic AKI via the NLRP6 Inflammasome Pathway
Session Information
- AKI: Mechanisms - Inflammation and Repair
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zhu, Yuqi, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
- Yu, Wenjuan, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
- Tang, Ying, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
Background
Sepsis is a major global health burden, accounting for 31.5% of global mortality. Sepsis-associated acute kidney injury (SA-AKI) affects 50–60% of critically ill patients and is linked to significantly increased mortality. The annexin A family (ANXA1–ANXA13) are calcium-dependent phospholipid-binding proteins that regulate membrane signaling, inflammation, and cell death, serving as key regulators in sepsis-induced target organ injury. ANXA3 is upregulated in septic patients and proposed as a diagnostic biomarker, however, its specific mechanism remains to be further investigated.
Methods
Proteomics analyses were performed on renal tissues from SA-AKI mice. Urinary ANXA3 levels were measured by ELISA. Renal tubule epithelial cell-specific ANXA3 knockout (ANXA3-cKO) mice were generated and subjected to cecal ligation and puncture (CLP)- and Lipopolysaccharide (LPS) induced SA-AKI. Renal function, histopathology, and pyroptosis markers (cleaved Caspase1, GSDMD-N, IL-1β) were assessed. Mechanistically, co-immunoprecipitation (Co-IP), GST pull-down, and immunofluorescence were used to detect ANXA3-NLRP6 binding and inflammasome assembly.
Results
Proteomics analysis showed significant upregulation of ANXA3 in the kidneys of SA-AKI mice, and multiplex immunofluorescence further localized to renal tubular epithelial cells. Notably, urinary ANXA3 levels correlated closely with disease severity. Renal tubule-specific deletion of ANXA3 ameliorated SA-AKI, as confirmed in renal tubular epithelial cell-specific ANXA3 knockout mice. Mechanistically, ANXA3 directly binds to NLRP6 and promotes its assembly, leading to NLRP6 oligomerization and subsequent inflammasome formation. This activates the NLRP6-Caspase1-GSDMD-IL1β signaling pathway, which mediates pyroptosis in renal tubular epithelial cells. Collectively, our findings indicate that ANXA3 exerts nephrotoxic effects in SA-AKI and may serve as a potential therapeutic target by modulating the NLRP6-Caspase1-GSDMD-IL1β signaling axis.
Conclusion
In conclusion, ANXA3 is upregulated in SA-AKI and exerts a detrimental role by directly binding to NLRP6 and promoting its assembly into an inflammasome. This activates the NLRP6-Caspase-1-GSDMD-IL-1β signaling axis, thereby inducing pyroptosis of renal tubular epithelial cells and exacerbating kidney injury. Thus, targeting ANXA3 may represent a novel therapeutic strategy for SA-AKI.
Acknowledgment
The authors thank the members of the laboratory for technical assistance with multi-omics data analysis and animal model generation.