Abstract
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.
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Data availability
All data relevant to the study are included in the article or uploaded as supplementary information. Additional supporting data are available from the corresponding authors upon reasonable request, and the raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2025) in National Genomics Data Center (Nucleic Acids Res 2025), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences53,54 (GSA-Human: HRA013828) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.
Code availability
All analyses were performed using conventional analysis code, which is available at https://github.com/carmonalab/GeneNMF55, and no new codes were generated.
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Acknowledgements
We acknowledge Yongchu Pan, Mifang Yang, Dongling Yan, and Linlin Jiang for the use of experimental instruments (Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University). The authors thank Prof. Zhi-Jun Sun for the kind gift of the time-inducible tissue-specific Tgfbr1/Pten 2cKO HNSCC mice. This research was funded by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant No. 23KJA320003).
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J.J.C.: Data curation, conceptualization, methodology, formal analysis, investigation, writing-original draft. Y.Y.: Data curation, methodology, formal analysis, investigation, writing-original draft. J.H.Z.: Data curation, formal analysis, methodology, investigation. Y.J.G.: Data curation, formal analysis, methodology. M.R.Z.: Data curation, formal analysis, investigation. R.Z.: Data curation, methodology. Y.H.L.: Investigation. J.Y.W.: Investigation. X.S.: Conceptualization, supervision, funding acquisition, project administration, resources, writing-review, and editing.
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Cui, JJ., Yang, Y., Zhao, JH. et al. NDUFA4L2 regulates the progression and chemotherapy sensitivity of HNSCC by inhibiting PANoptosis. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01358-5
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DOI: https://doi.org/10.1038/s41698-026-01358-5
