Abstract

Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck tissues. Disulfidptosis is a novel form of programmed cell death caused by disulfide stress, which mainly manifests as cytoskeleton protein and F-actin breakdown. In this study, we collected 504 HNSCC patients’ data from The Cancer Genome Atlas (TCGA) database and constructed a prognostic disulfidptosis-related gene signature for HNSCC patients. Destrin (DSTN), an actin depolymerizing factor, was considered a reliable prognostic biomarker, with its high expression significantly associated with shorter overall survival (OS) and progression-free survival (PFS). Functional enrichment analysis revealed that DSTN was positively correlated with extracellular matrix (ECM)-related genes, and particularly enriched in ECM degradation pathways and matrix metalloproteinase (MMP) family members, such as MMP10 and MMP3. qPCR and Western blot results showed that knockdown of DSTN inhibited the expression of ECM-related genes MMP10 and MMP3 in HNSCC cells. Tumor immune microenvironment analysis revealed that DSTN was negatively correlated with infiltration levels of various immune cells, immune checkpoints, and tumor mutational burden (TMB). Co-culture experiment of H9 cells with HNSCC cells further demonstrated that DSTN knockdown significantly upregulated the CD274 expression in HNSCC cells. In vitro functional experiments showed that DSTN knockdown effectively inhibited HNSCC cell proliferation and migration, suppressed glucose metabolism, and blocked Wnt/β-catenin signaling pathway activation; additionally, it induced F-actin contraction, triggering disulfidptosis. In vivo xenograft experiments confirmed that DSTN knockdown significantly inhibited HNSCC tumor growth. In conclusion, this study demonstrates that DSTN is a key driver promoting the malignant progression of HNSCC; high DSTN expression indicates poor prognosis, while its downregulation exerts tumor-suppressive effec