Mechanistic study on comorbidities of kidney stones and sepsis using transcriptome sequencing combined with...

Kidney stones and sepsis have a complex pathological association. Urinary obstruction and infection caused by kidney stones can easily induce sepsis, leading to increased mortality and poor prognosis. However, the molecular mechanism underlying their comorbidity remains unclear, and there is a lack of specific biomarkers for early prediction and targeted therapy. This study aims to explore the molecular regulatory network of their comorbidity, screen key genes, and clarify their roles in disease progression. Transcriptome, single-cell ribonucleic acid sequencing (scRNA-seq), and spatial transcriptome data of kidney stones and sepsis were downloaded from the Gene Expression Omnibus database. Differential expression analysis was performed using the Limma package to screen for shared differentially expressed genes between the 2 diseases. Least absolute shrinkage and selection operator regression and random forest algorithms were applied for feature selection to identify key regulatory genes. Functional enrichment analyses (Gene Ontology, KEGG) were conducted to explore biological processes and signaling pathways associated with these genes. ScRNA-seq was used to determine cell-type-specific expression patterns, while spatial transcriptome combined with robust cell-type decomposition was employed to validate their spatial distribution. Additionally, transcriptional regulation analysis, drug-gene interaction prediction (via DGIdb), and molecular docking were performed to investigate potential regulatory mechanisms and therapeutic targets. Five key genes (FCER1A, LEF1, NELL2, SBK1, ZC3H8) were identified through integrative analysis. Functional enrichment showed these genes are primarily involved in bacterial response, immune effector processes, and inflammation-related pathways such as IL6-JAK-STAT3 signaling. ScRNA-seq revealed cell-type specificity: FCER1A was enriched in immune cells, LEF1 localized to T cells, and NELL2 was highly expressed in renal tubular epithelial cells. Spatial transcriptome and robust cell-type decomposition confirmed their spatial distribution - NELL2 was overexpressed in epithelial-damaged regions of kidney stones, while FCER1A accumulated around blood vessels in sepsis. Transcriptional regulation analysis indicated FCER1A is regulated by the cisbp__M2925 motif. DGIdb predicted 14 potential drugs targeting FCER1A, and molecular docking showed a binding energy of -5.0 kcal/mol between FCER1A (1j88) and ROME. This study identified 5 key genes and their regulatory networks in the comorbidity of kidney stones and sepsis, revealing their roles in immune regulation and inflammatory responses.