Hao Lin, Xinran Cheng, Yangyang Ren, Yongmei Zhang, Weixu Chen, Qingyan Lu, Yiqing Tian
Our study demonstrates that FAP+ CAFs orchestrate a dual-functional "immunosuppressive stem cell niche" via the COL1A1/2-CD44 signaling axis. Targeting this FAP-driven niche provides a promising strategy for overcoming immunotherapy resistance and improving clinical outcomes in CC.
High‑throughput transcriptomic technologies offer a systems‑level approach to unravel the mechanisms of complex immune disorders. Inflammatory Bowel Disease (IBD), a classic example of such disorders, involves intricate interactions between genetics, microbiota and immune dysfunction. The nuclear receptor farnesoid X receptor (FXR) is implicated in IBD, but its precise mechanisms remain unclear. To investigate the role of FXR in ulcerative colitis (UC), the present study employed an integrative transcriptomic strategy, combining bulk transcriptomics (GSE75214, GSE13367 and GSE87466) and single‑cell RNA‑sequencing data (GSE116222) of human UC samples obtained from the Gene Expression Omnibus database. Subsequently, these findings were validated in a dextran sulfate sodium‑induced colitis model using FXR global knockout mice. The results revealed that FXR expression is downregulated in UC and co‑localizes with the stem cell marker CD133 in intestinal crypts. FXR deficiency exacerbated dextran sulfate sodium‑induced colitis, impaired the expression of stemness‑associated transcription factors (octamer‑binding transcription factor 3/4, homeobox protein NANOG, transcription factor SOX2 and Sal‑like protein 4), and activated the NF‑κB pathway, leading to increased production of pro‑inflammatory cytokines, specifically TNF‑α and IL‑1β. By integrating bulk and single‑cell transcriptomics with genetic validation, the present study uncovered an FXR‑dependent mechanism linking intestinal stem cell dysfunction to NF‑κB‑driven inflammation in colitis, and established a generalizable multi‑layer transcriptomic dissection strategy for complex inflammatory disorders.