Kidney Week

Abstract: TH-PO0342

DEAD-Box Helicase 41 (DDX41) as a Candidate Driver of Podocyte Injury

Session Information

• Glomerular Diseases: Omics
  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

• Nguyen, Minh Hieu, Case Western Reserve University, Cleveland, Ohio, United States

Minh Hieu Nguyen

• Kim, Najeong, Case Western Reserve University, Cleveland, Ohio, United States

Najeong Kim, MS

• Jadhav, Darshan, Case Western Reserve University, Cleveland, Ohio, United States

Darshan Jadhav, MSc

• Gonzalez-Vicente, Agustin, Case Western Reserve University, Cleveland, Ohio, United States

Agustin Gonzalez-Vicente, PhD

Group or Team Name

• for the Kidney Precision Medicine Project

Background

Innate immune activation in podocytes (PODs) is a driver of glomerular injury and POD loss. Different cytosolic DNA sensors can signal through the stimulator of interferon genes (STING) triggering proinflammatory responses. DDX41 physically interacts with STING facilitating signalosome assembly. We hypothesized that DDX41 is a driver of POD degeneration through STING.

Methods

We studied gene expression in the POD cluster from the Kidney Precision Medicine Project (KPMP) single-nucleus RNA sequencing (snRNAseq) Human Kidney Atlas 2.0. The cluster contained 16,137 cells of which 24% were degenerative (d)PODs. A POD↔dPOD slingshot axis was created and pseudobulk counts were extracted across degeneration progression quantiles. DDX41 and phosphorylated (p)-STING(Ser366) were measured by Western blots in primary cultures of human PODs (Celprogen) treated with 30mM Glucose + 150µM palmitate for 12hs (Control: 5mM Glucose + 25mM Sorbitol + albumin carrier).

Results

At the whole-cluster level DDX41-UMI-positive (+) cells were over-represented (Fisher: OR=1.95; p≤1.2x10^-11) in the dPOD fraction (DDX41+ =4.73%) relative to PODs (DDX41+ =2.48%). Moreover, binned-eGFR correlated with the fraction of dPOD (Spearman= -0.16, p≤0.28). At the patient-level, DDX41+ cells correlated with the fraction of dPOD (Spearman= +0.29, p≤1.04x10^-5) indicating that whole-cluster results are not outlier driven. Pseudobulk DDX41 expression increased along the POD-degeneration axis from the 1^st (POD-rich) to 5^th (dPOD-rich) quantile. In contrast, transcripts encoding slit diaphragm proteins and identity/protective transcription factors declined (Table 1). Transcripts of the canonical DNA sensor cGAS remained unchanged. Metabolically stressed POD cultures (n=4), showed increased DDX41 (Δ=35%; p≤0.05) and p-STING (Δ=42%; p≤0.05) abundance.

Conclusion

DDX41 expression increases along the podocyte degeneration axis while cGAS does not. This positions DDX41 as a non-canonical DNA sensor upstream of STING in podocyte injury. Additional mechanistic studies are needed to establish causality.

Acknowledgment

This work was partially funded by NIH-NIDDK (DK128304) and Diabetes Recersch Connection (DRC074) research grants to A G-V.

Binned pseudobulk counts along the POD degeneration axis

Funding

• NIDDK Support