New mitotic mechanisms are significantly associated with cisplatin resistance, with MSRB3, RHEB, ULBP1, and SPC25 correlating with poor prognosis in HNC patients. The study further shows that silencing SPC25 significantly suppresses tumor stemness and reduces cisplatin resistance. The natural extract Celastrol effectively inhibits SPC25 expression and reverses the cisplatin resistance phenotype. Here, SPC25 is linked to neoplasm.