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Nasopharyngeal carcinoma (NPC), a malignancy prevalent in East Asia, is primarily treated with radiotherapy; however, radioresistance remains a major challenge, leading to recurrence and poor outcomes. While FGFs are known to activate signaling pathways such as MAPK, PI3K\/AKT, and JAK\/STAT to promote cancer progression, the specific role of individual FGFs in NPC radioresistance remains unclear. Emerging evidence highlights FGF5 as a key player in NPC progression, metastasis, and radioresistance, underscoring its potential as a therapeutic target to overcome treatment resistance and improve clinical outcomes. Methods: We analyzed single nucleotide variation (SNV) data, gene expression, and DNA methylation patterns using cancer datasets, including TCGA and GTEx, to investigate FGF5 expression. Differentially expressed genes (DEGs) were identified and interpreted using functional enrichment analysis, while survival analysis and gene set enrichment analysis (GSEA) were conducted to identify clinical correlations. DNA methylation patterns were specifically assessed using the HumanMethylation850 BeadChips on tissue samples from nine recurrent and nine non-recurrent NPC patients. Functional assays, including cell viability, migration, invasion, and clonogenic survival assays, were performed to evaluate the effects of FGF5 on NPC cell behavior in vitro and in vivo. Results: FGF5 showed elevated SNV frequencies across multiple cancers, particularly in HNSC and NPC. DNA methylation analysis revealed an inverse relationship between FGF5 expression and methylation levels in recurrent NPC tumors. Functional assays demonstrated that FGF5 enhances migration, invasion, and radioresistance in NPC cells. High FGF5 expression was associated with reduced distant metastasis-free survival (DMFS) and increased radioresistance, highlighting its role in metastatic progression and recurrence. Conclusions: FGF5 plays a significant role in the progression and recurrence of nasopharyngeal carcinoma. Its elevated expression correlates with increased migration, invasion, and radioresistance as well as reduced distant metastasis-free survival. These findings suggest that FGF5 contributes to the metastatic and recurrence potential of NPC, making it a potential target for therapeutic intervention in treating these cancers.<\/jats:p>","DOI":"10.3390\/biom15020283","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T04:48:51Z","timestamp":1739508531000},"page":"283","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Multi-Omics Characterization of Genome-Wide Abnormal DNA Methylation Reveals FGF5 as a Diagnosis of Nasopharyngeal Carcinoma Recurrence After Radiotherapy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0704-7947","authenticated-orcid":false,"given":"Zhi-Qing","family":"Long","sequence":"first","affiliation":[{"name":"Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3564-1142","authenticated-orcid":false,"given":"Ran","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Qiu","family":"Quan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo-Hui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2259-8958","authenticated-orcid":false,"given":"Denghui","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5888-2929","authenticated-orcid":false,"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1158\/1055-9965.EPI-20-1702","article-title":"The evolving epidemiology of nasopharyngeal carcinoma","volume":"30","author":"Chang","year":"2021","journal-title":"Cancer Epidemiol. 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