Purpose <p>Cancer-associated fibroblasts (CAFs), a crucial component of tumor microenvironment, play a critical role in tumorigenesis, progression, and conferring resistance to radiotherapy and chemotherapy. This study aimed to investigate the association between CAFs, CAF- related genes, and radioresistance in hepatocellular carcinoma (HCC).</p> Methods <p>CAFs were isolated from HCC tissues and subsequently utilized for co-culturing with HCC cells using CAFs-conditioned medium. An orthotopic HCC mouse model was established by co-implanting CAFs and HCC cells. Through integrative analysis of three RNA-sequencing datasets (TCGA-LIHC tumor vs. normal tissues, Huh7 radioresistant vs. parent cells, and CAF vs. control group), CAF-associated prognostic genes were identified using comprehensive bioinformatics approaches. Experimental validation was performed by real-time quantitative PCR, western blot, immunohistochemistry, cell viability assays, and colony formation assays.</p> Results <p>Our findings demonstrated that CAFs significantly enhance radioresistance in HCC. Based on 13 CAF-related prognostic genes, TCGA-LIHC patients were stratified into two distinct clusters via consensus clustering, exhibiting significant differences in overall survival, immune cell infiltration, and therapeutic response. A prognostic nomogram incorporating three hub genes and clinical characteristics was developed. Notably, SOX4 was upregulated in tumor tissues, radioresistant cells, and CAF-exposed HCC cells, correlating with poor prognosis. SOX4 knockdown suppressed HCC proliferation and reversed CAF-induced radioresistance. Additionally, a competitive endogenous RNA (ceRNA) network of LINC00665/miR-122-5p/SOX4 was constructed.</p> Conclusion <p>CAFs serve as crucial mediators of radioresistance in HCC, and CAF-related genes provide valuable prognostic and therapeutic insights. SOX4 emerges as a promising therapeutic target to improve radiotherapy efficacy in HCC.</p> Clinical trial number <p>Not applicable.</p>