SERPINH1 derived from cancer-associated fibroblasts promotes epithelial-mesenchymal transition in clear cell renal cell carcinoma

Despite advances in cancer treatment, the prognosis of clear cell renal cell carcinoma (ccRCC) remains poor. The role of CAFs in ccRCC remains unclear. The single-cell sequencing (scRNA-seq) data for ccRCC were downloaded from the GEO database, with the SERPINH1⁺ fibroblast subpopulation identified. Cancer-associated fibroblasts (CAFs) were determined. In vitro assays analyzed SERPINH1 expression and its impact on ccRCC tumor progression. In vivo animal experiments validated SERPINH1 function. The scRNA-seq data analysis demonstrated that ccRCC cells showed remarkable intratumoral heterogeneity. CAFs were an important source of SERPINH1 in ccRCC, which was further verified in CAFs isolated from tumor tissue. In cell experiments, SERPINH1 from CAFs promoted the up-regulation of TGF-β to induce EMT in ccRCC cells, and TGF-β from tumor cells reinforced the secretion of SERPINH1 from CAFs to form a feedback loop. In vivo experiments elucidated the effects of blocking SERPINH1 function on ccRCC malignant progression. CAFs, as the communication center of TME in ccRCC, secrete SERPINH1 to elevate TGF-β level in tumor cells, and influence epithelial-mesenchymal transition (EMT) and malignant progression of ccRCC. The research helps to elucidate the tumor-promoting mechanism of CAFs and provides a new therapeutic strategy for repressing CAF activation.