● FGF2 and EREG mRNA were increased in cisplatin-treated ALDHhigh CD44high● TNFα, IFNγ, IL-6, and NF-κB signaling pathways were associated with cisplatin resistance in ALDHhigh CD44high cells● FGFR1-4 inhibition, together with cisplatin treatment, promoted a 50% reduction in ALDHhigh CD44high● After FGFR2 knockdown, cisplatin no longer increased the ALDHhigh CD44high CSC in HNSCC cell lines● Therapeutic inhibition of FGFR might contribute to eliminating ALDHhigh CD44high cisplatin-resistant CSCs. Here, EREG is linked to head and neck squamous cell carcinoma.