SERPINE1 promotes HNSCC progression and cisplatin resistance by upregulating CA9

Head and neck squamous cell carcinoma (HNSCC) has an unfavorable prognosis and lacks effective molecular targets. In this study, we systematically profiled the SERPIN family in HNSCC and, based on TCGA analyses, identified SERPINE1 as the primary gene of interest. Stable SERPINE1 knockdown and overexpression models were established in HNSCC cells, and its oncogenic effects were confirmed by in vitro functional assays assessing proliferation, migration, and invasion, together with subcutaneous nude mouse xenograft models. Transcriptome sequencing further identified CA9 as a key downstream effector of SERPINE1. Mechanistically, using cisplatin-resistant FaDu-CDDP and Tu686-CDDP cells, IC50 determination and rescue experiments showed that SERPINE1 and CA9 were concomitantly upregulated in resistant cells; silencing either gene attenuated cisplatin resistance, whereas restoration of CA9 in SERPINE1-depleted cells reversed the inhibitory phenotypes and reinstated cisplatin resistance. Collectively, these findings demonstrate that SERPINE1 promotes HNSCC progression and cisplatin resistance through upregulation of CA9, supporting the SERPINE1–CA9 axis as a potential prognostic biomarker and therapeutic target in HNSCC.