Integrative Multiomics and Single-Cell Analyses Identify FKBP10 as a Predictor of Radiotherapy Outcome in Colorectal Cancer

<h4>Background</h4>Radiotherapy resistance limits colorectal cancer (CRC) treatment efficacy, with only 15%-20% of patients achieving a complete response. Validated biomarkers predicting treatment response and serving as therapeutic targets are critically needed.<h4>Methods</h4>We performed integrative multiomics analysis of 200 CRC patients (GSE87211) with independent validation in 58 patients (GSE46862). Single-cell RNA sequencing of 63,689 cells (GSE132465) determined cell-type-specific expression. Functional validation was conducted in radiotherapy-resistant CRC cell lines through loss-of-function experiments including proliferation, migration/invasion, and radiosensitivity assays.<h4>Results</h4>FKBP10 emerged as the only gene achieving statistical significance in both discovery (log2FC = 0.74, <i>p</i> = 0.0007) and validation (log2FC = 0.52, <i>p</i> = 0.032) cohorts among 48 radioresistance-associated genes. Single-cell profiling revealed that FKBP10 was predominantly expressed in cancer-associated fibroblasts (CAFs, 51.5% of stromal cells), implicating CAF-mediated stromal remodeling in resistance. FKBP10 knockdown significantly inhibited proliferation, colony formation (35%-40% reduction), migration (30%), and invasion (50%), while markedly enhancing radiosensitivity through increased DNA damage (<i>γ</i>H2AX foci increased twofold, <i>p</i> < 0.01) and strand breaks (comet tail DNA: 22% → 43%, <i>p</i> < 0.01).<h4>Conclusions</h4>This multiomics study establishes FKBP10 as a robust CAF-derived biomarker and functional therapeutic target for radiotherapy resistance in CRC, providing a foundation for developing FKBP10-targeted combination strategies for precision cancer treatment.