Multi-Omics Integration Identifies TNFRSF1A as a Causal Mediator of Immune Microenvironment Reprogramming in Diabetic Kidney Disease

Xie, Wanqiu; Zhao, Dongfang; Franz, Henriette; Schmitt, Annette; Walz, Gerd; Yakulov, Toma A.

doi:10.3390/ijms27010279

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Multi-Omics Integration Identifies TNFRSF1A as a Causal Mediator of Immune Microenvironment Reprogramming in Diabetic Kidney Disease

by

Wanqiu Xie

¹,

Dongfang Zhao

¹,

Henriette Franz

²,

Annette Schmitt

¹,

Gerd Walz

^1,3 and

Toma A. Yakulov

^1,*

¹

Renal Division, University Freiburg Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany

²

Department of Biomedicine, University of Basel, CH-4056 Basel, Switzerland

³

Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79106 Freiburg, Germany

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(1), 279; https://doi.org/10.3390/ijms27010279 (registering DOI)

Submission received: 24 November 2025 / Revised: 24 December 2025 / Accepted: 25 December 2025 / Published: 26 December 2025

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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Abstract

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide. However, the inflammatory mediators that causally drive disease progression remain incompletely defined. In this study, we used a multi-omics approach that combined single-cell RNA sequencing, spatial transcriptomics, pseudotime trajectory analysis, cell-to-cell communication analysis, and Mendelian randomization (MR) to investigate the role of tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in DKD development. Findings were further validated in zebrafish embryos depleted of pdx1, an established model of DKD. Spatial transcriptomic analysis showed that TNFRSF1A is enriched in cortical kidney regions. Pseudotime analysis revealed progressive immune reprogramming, with an early predominance of T and NK cells and gradual shift to myeloid infiltration and B-cell expansion. Cell-to-cell communication analysis highlighted IL-1β and related signaling pathways that increase NF-κB activity. Mendelian Randomization analysis, complemented by PPI network mapping, identified TNFRSF1A (OR = 1.78, 95% CI: 1.17–2.71, p = 0.007) as a gene with genetic evidence supporting a causal association. Consistent with the human data, experiments in zebrafish showed that tnfrsf1a expression increases significantly following pdx1 knockdown (p = 0.0025). Together, these findings support a role for TNFRSF1A in immune microenvironment reprogramming in DKD, while not excluding the involvement of additional regulatory pathways.

Keywords: diabetic kidney disease; TNFRSF1A; single-cell transcriptomics; Mendelian randomization; immune microenvironment; zebrafish model; inflammation; NF-κB signaling

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MDPI and ACS Style

Xie, W.; Zhao, D.; Franz, H.; Schmitt, A.; Walz, G.; Yakulov, T.A. Multi-Omics Integration Identifies TNFRSF1A as a Causal Mediator of Immune Microenvironment Reprogramming in Diabetic Kidney Disease. Int. J. Mol. Sci. 2026, 27, 279. https://doi.org/10.3390/ijms27010279

AMA Style

Xie W, Zhao D, Franz H, Schmitt A, Walz G, Yakulov TA. Multi-Omics Integration Identifies TNFRSF1A as a Causal Mediator of Immune Microenvironment Reprogramming in Diabetic Kidney Disease. International Journal of Molecular Sciences. 2026; 27(1):279. https://doi.org/10.3390/ijms27010279

Chicago/Turabian Style

Xie, Wanqiu, Dongfang Zhao, Henriette Franz, Annette Schmitt, Gerd Walz, and Toma A. Yakulov. 2026. "Multi-Omics Integration Identifies TNFRSF1A as a Causal Mediator of Immune Microenvironment Reprogramming in Diabetic Kidney Disease" International Journal of Molecular Sciences 27, no. 1: 279. https://doi.org/10.3390/ijms27010279

APA Style

Xie, W., Zhao, D., Franz, H., Schmitt, A., Walz, G., & Yakulov, T. A. (2026). Multi-Omics Integration Identifies TNFRSF1A as a Causal Mediator of Immune Microenvironment Reprogramming in Diabetic Kidney Disease. International Journal of Molecular Sciences, 27(1), 279. https://doi.org/10.3390/ijms27010279

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Multi-Omics Integration Identifies TNFRSF1A as a Causal Mediator of Immune Microenvironment Reprogramming in Diabetic Kidney Disease

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