SLC25A1 upregulation promotes HNSCC cisplatin resistance via H3K27ac-mediated cellular senescence

Chemoresistance to cisplatin is a major contributor to the progression of head and neck squamous cell carcinoma (HNSCC); however, the mechanisms underlying cisplatin resistance in HNSCC remain incompletely understood. Dysregulation of metabolite transport between mitochondria and the cytoplasm, mediated by solute carrier family 25 (SLC25), is closely associated with tumor progression. Solute carrier family 25 member 1 (SLC25A1) promotes malignant phenotypes in various cancers; however, its role in HNSCC remains unexplored. Here, we demonstrate that SLC25A1 is overexpressed in HNSCC and is closely associated with poor prognosis. SLC25A1 upregulation promotes cisplatin resistance in HNSCC cells. Moreover, SLC25A1 enhances cisplatin resistance in HNSCC cells by inducing cellular senescence. Mechanistically, SLC25A1 upregulates the expression of RANBP1, CDC45, and PES1 through histone H3 lysine 27 acetylation-mediated transcriptional activation. Furthermore, SLC25A1 interacts with HSPD1, a mitochondrial chaperonin protein, via its C-terminal region to increase citrate transport and cytosolic acetyl-CoA levels. Treatment with CTPI-2, a specific inhibitor of SLC25A1, exhibits therapeutic effects against cisplatin-resistant HNSCC. These findings establish SLC25A1 as a key regulator of cisplatin resistance in HNSCC, suggesting that it serves as both a predictive biomarker and a potential therapeutic target in chemoresistant HNSCC. From a translational perspective, these results support CTPI-2 as a promising therapeutic agent for overcoming cisplatin resistance.