Integrated spatial and single‑cell transcriptomics maps disulfidptosis in renal cell carcinoma and reveals PDLIM1 as...

Disulfidptosis is a regulated cell death program linked to redox stress, metabolism, and the actin cytoskeleton. Its organization in tissue and clinical relevance in renal cell carcinoma are not well defined.

We integrated spatial transcriptomics from six renal cancer sections with four single cell RNA sequencing cohorts. Disulfidptosis scores were computed, RCTD deconvolution and epithelial reclustering were used to localize subpopulations, and pathway enrichment and CytoTRACE assessed metabolism and stemness. External validation used TCGA-KIRC, KIRP and additional public datasets. Candidate genes were nominated by intersecting disulfidptosis, Cluster 3, and Epi_C5 signatures. PDLIM1 function was tested by sh-RNA in renal cancer cell lines with qPCR, proliferation, wound healing, and Transwell assays.

Disulfidptosis showed strong intra heterogeneity. Spatial clusters 2, 3, and 6 were enriched, with Cluster 3 higher in tumors and linked to worse survival, and Cluster 6 context dependent yet adverse. Signals localized mainly to epithelial cells. Epithelial reclustering identified Epi_C5 with the highest disulfidptosis and Cluster 3 scores. Disulfidptosis-high cells were enriched for N glycan biosynthesis, purine and pyrimidine metabolism, oxidative phosphorylation, and nitrogen metabolism, with spatial overlap between nitrogen metabolism and disulfidptosis. Epi_C5 upregulated extracellular matrix programs, showed higher CytoTRACE, and associated with poor prognosis in both TCGA cohorts. Intersecting signatures nominated PDLIM1, which was tumor elevated and correlated with Epi_C5 and CytoTRACE. PDLIM1 knockdown reduced proliferation, and migration.

We define a disulfidptosis‑associated epithelial malignant state in renal cancer and nominate PDLIM1 as a candidate node for patient stratification and therapeutic development.