Abstract: TH-PO0431
C5a Synergistically Enhances STING Signaling to Promote Podocyte Injury in FSGS
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
- Qi, Enyu, Xiangya Hospital Central South University, Changsha, Hunan, China
- Li, Xiaozhao, Xiangya Hospital Central South University, Changsha, Hunan, China
Background
Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage kidney disease, with podocyte injury as its central pathological feature. Innate immune pathways, including TLR signaling, NLRP3 inflammasome activation, and complement activation, have been implicated in FSGS progression. Although IFN-I signaling has been linked to interferon-associated podocytopathies, its upstream regulatory pathway in FSGS remains incompletely defined. The cGAS-STING pathway senses cytosolic DNA and induces IFN-I production. C5a-C5aR1 signaling is also involved in immune regulation in glomerular diseases, but its relationship with STING signaling in FSGS remains unclear. This study investigated the role of STING signaling in FSGS-related podocyte injury and its potential link with C5a signaling.
Methods
GEO transcriptomic data were analyzed to assess IFN-I and cGAS-STING activation in FSGS glomeruli. Plasma cGAMP and urinary IFN-α/IFN-β were measured in patients with FSGS, MCD, MN, and healthy controls. Renal STING expression and its colocalization with synaptopodin were examined by immunofluorescence. ADR-induced FSGS mice were treated with C-176, diABZI, STING knockout, or PMX53. Cultured mouse podocytes were treated with ADR, C5a, PMX53, or STING siRNA to assess STING signaling and podocyte marker expression.
Results
(1) IFN-I signaling and the cGAS-STING pathway were activated in FSGS glomeruli. Patients with FSGS showed increased plasma cGAMP, urinary IFN-α/IFN-β, and renal STING expression. STING colocalized with synaptopodin. (2) In ADR-induced FSGS mice, STING-TBK1-IRF3 activation accompanied podocyte injury and proteinuria. STING inhibition or knockout reduced IFN-I expression and renal injury, whereas STING activation caused acute kidney injury.(3) In podocytes, ADR activated STING signaling and reduced podocin. STING knockdown partially restored podocin.(4) IFN-I-related gene activity was positively associated with complement-related genes, and C5a levels correlated with cGAMP and IFN-I levels in FSGS. PMX53 partially suppressed STING signaling and alleviated podocyte injury in vivo. C5a enhanced STING signaling in ADR-treated podocytes, whereas PMX53 partially reversed this effect and improved podocyte protein expression.
Conclusion
The cGAS-STING-IFN-I axis is activated in FSGS and contributes to podocyte injury. C5a-C5aR1 signaling may amplify STING-mediated activation and aggravate podocyte injury.