Given the role of PHF5A in the generation of DOCK5 variants, this study demonstrated that PHF5A activated the p38 MAPK pathway in HNSCC, with increases in p-p38, p-HSP27, p-MSK1, p-MAPKAPK2, p-ATF2 and p-MEK3. Here, MAPKAPK2 is linked to head and neck squamous cell carcinoma.