ArticleFrontiers in immunology2026
Identification of PANoptosis hub genes driving immune activation and tubulointerstitial injury in diabetic kidney disease by integrative bioinformatics and machine learning.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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9 authors.
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Abstract
Background: Diabetic kidney disease (DKD) is characterized by chronic inflammation and immune dysregulation. Multiple programmed cell death pathways contribute to tubulointerstitial injury, but their perturbations, crosstalk, and integrative impact in DKD remain unclear. PANoptosis-a coordinated program integrating pyroptosis, apoptosis, and necroptosis-has emerged as a key mechanism in inflammatory disorders, yet its role in DKD is not defined. Methods: We integrated multiple renal tubulointerstitial transcriptomic datasets from DKD and control cohorts to identify differentially expressed genes, followed by functional enrichment analysis. PANoptosis-related gene sets were curated from MSigDB, and pathway crosstalk was evaluated using independent single-cell RNA-seq datasets. Hub genes were prioritized by combining weighted gene co-expression network analysis (WGCNA) with five machine-learning algorithms, and a PANoptosis-related risk score (PRS) was constructed and correlated with clinical parameters and immune infiltration. miRNA-mRNA and transcription factor-hub gene regulatory networks were inferred using ENCORI and hTFtarget, respectively. Druggability of hub genes was assessed using DrugnomeAI, and candidate compounds were retrieved from DGIdb. Key findings were validated in diabetic mouse models. Results: Apoptosis, pyroptosis, necroptosis and the integrated PANoptosis program were markedly activated in DKD. At the single-cell level, these pathways were frequently co-activated within tubular and interstitial cell types, with extensive molecular overlap. Six PANoptosis-related hub genes ( Conclusion: This study delineates extensive perturbations and crosstalk among apoptosis, pyroptosis and necroptosis in DKD, positioning PANoptosis as a unifying driver of tubulointerstitial injury. The six PANoptosis hub genes and their derived PRS show strong diagnostic potential, while integrated regulatory and druggability analyses nominate
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