Abstract: TH-PO0434
Niclosamide Enhances Production of Galactose-Deficient IgA1 via Suppression of NF-κB p65 and pSTAT3 in Immortalized B Cells from Patients with IgAN and Healthy Controls
Session Information
- Glomerular Diseases: Autoimmune Diseases
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Reily, Colin, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Julian, Bruce, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Rizk, Dana V., University of Alabama at Birmingham, Birmingham, Alabama, United States
- Novak, Jan, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background
Galactose-deficient IgA1 (Gd-IgA1) is an autoantigen driving formation of pathogenic immune complexes in IgA nephropathy (IgAN), but B-cell pathways governing its production remain incompletely defined. Genome-wide association studies (GWAS) of IgAN identified multiple NF-kB-related loci. These discoveries prompted us to test various NF-κB inhibitors for their effects on Gd-IgA1 production. We previously showed that the IKK-β inhibitor TPCA-1 increased Gd-IgA1 production by EBV-immortalized B cells by suppressing NF-κB p65 activation. Additionally, we found that niclosamide, an FDA-approved anthelminthic that uncouples mitochondria and inhibits NF-κB p65, substantially increased Gd-IgA1 production.
Methods
EBV-immortalized B-cell lines from IgAN patients and healthy controls were treated with niclosamide (1 µM) or FCCP (carbonyl cyanide p-trifluoromethoxyphenylhydrazone, mitochondrial uncoupler; 0.5 µM), for 48 h. Production of IgA and Gd-IgA1 was quantified by ELISA and lectin ELISA with sialidase treatment (n=8). Cellular NF-κB p65, pSTAT3 (Y705), and IgA were quantified by imaging flow cytometry at 48 h (n=5).
Results
Niclosamide reduced total IgA secretion (n=8; mean 84% and median 82% reduction, p<0.01), whereas FCCP showed a trend for decreased secretion. Niclosamide increased Gd-IgA1/IgA ratio for all tested cells, with a mean of 15- and median of 11-fold increase over control (p<0.01). FCCP showed variable effects across cell lines. Imaging flow cytometry of IgA1-positive cells at 48 h showed that niclosamide (1 µM) decreased the percentage of cells with nuclear NF-κB p65 from 77.9% to 32.0% and reduced p65 nuclear-translocation intensity from 1.32 to 0.70 (p<0.01, n=5); pSTAT3 MFI also fell 49% on average (p=0.01).
Conclusion
Niclosamide induced Gd-IgA1 overproduction in IgAN- and healthy-control-derived B cells at concentrations that suppressed NF-κB p65 nuclear translocation and pSTAT3 activation. FCCP did not universally increase Gd-IgA1, suggesting that NF-κB suppression, and potentially pSTAT3, not uncoupling per se, is the proximal driver of autoantigen production. Notably, the enhanced Gd-IgA1 production induced by niclosamide vastly exceeded that induced by TPCA-1 (typically around 125%), suggesting additive effects of other targets that may include mitochondrial metabolism.
Funding
- NIDDK Support