NDUFA4L2 regulates the progression and chemotherapy sensitivity of HNSCC by inhibiting PANoptosis

Head and neck squamous cell carcinoma (HNSCC) represents a leading global malignancy among head and neck cancers. While chemotherapy serves as a standard Adjuvant treatment, cisplatin resistance frequently compromises therapeutic outcomes. PANoptosis is an integrated inflammatory cell death pathway governed by PANoptosome complexes. It critically influences chemotherapy response, though its regulatory mechanisms remain incompletely characterized. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2), a subunit of respiratory chain complex I, has been identified as a critical regulator of cell survival. Our multi-platform investigation employed HNSCC cell lines, patient-derived organoids, tongue orthotopic xenograft models in C57BL/6 mice and Tgfbr1/PTEN 2cKO mice to elucidate the role of NDUFA4L2 in cisplatin resistance. Bioinformatic analysis and clinical samples indicate that elevated NDUFA4L2 is associated with poor survival rates and low sensitivity to chemotherapy in HNSCC patients. Through in vitro and in vivo studies, we found that NDUFA4L2-KO in combination with cisplatin suppresses glycolysis levels, thereby inhibiting AIM2 inflammasome activation. Consequently, it triggers tumor cell PANoptosis, remodels the immunosuppressive tumor microenvironment, and enhances antitumor efficacy. These findings establish NDUFA4L2 as both a prognostic biomarker and therapeutic target for overcoming cisplatin resistance in HNSCC through PANoptosis modulation.