SPINK5 promotes sensitivity to cisplatin by inducing ferroptosis in head and neck carcinoma.

Cisplatin resistance remains a major obstacle in treating head and neck squamous cell carcinoma (HNSCC). Understanding its regulatory mechanisms is critical for improving therapeutic outcomes. SPINK5 expression was analyzed using TCGA datasets and tissue microarrays. Functional assays, including CCK-8, Annexin V-FITC/PI, and ferroptosis-specific probes (FerroOrange, DCFH-DA), were performed in SPINK5-overexpressing and FTH1-silenced HNSCC cells. Transcriptomic data were processed using R packages, with GSEA/GSVA for pathway analysis. Xenograft models were used to evaluate in vivo cisplatin responses. SPINK5 was significantly downregulated in HNSCC and correlated with poor prognosis and lymph node metastasis. Overexpression of SPINK5 enhanced cisplatin sensitivity by inducing ferroptosis, characterized by elevated ROS and Fe²⁺ levels, independent of classical apoptosis pathways. Unsupervised clustering and transcriptomic analysis identified FTH1 as a key downstream target of SPINK5. Mechanistically, SPINK5 suppressed FTH1 expression, promoting ferroptotic cell death and improving cisplatin efficacy in vitro and in vivo. SPINK5 functions as a tumor suppressor and sensitizes HNSCC cells to cisplatin by regulating ferroptosis via FTH1 downregulation, highlighting a novel therapeutic axis to overcome chemoresistance.