DHRS2 as a Novel Thalidomide Target Regulating Mitophagyand Inflammation in Head and Neck Squamous Cell Carcinoma

Background: Radiation Therapy (RT) in Head and Neck Squamous Cell Carcinoma (HNSCC) often induces inflammation. Here, we examined the relationship between mitophagy and inflammation in HNSCC. Methods: The Cancer Genome Atlas and Gene Expression Omnibus were analyzed to identify genes associated with HNSCC, mitophagy, inflammation, and Thalidomide (THD). Differentially Expressed Genes (DEGs) were evaluated for functional enrichment. A prognostic model was constructed using LASSO and COX regression and evaluated using Kaplan-Meier analysis. Based on its reported role in alleviating Radiation-Induced Oral Mucositis (RIOM) and inflammation, THD was assessed using molecular docking to further investigate its potential mechanism. Knockdown cell lines were generated to examine the function of dehydrogenase/reductase 2 (DHRS2). results: In this study, mitochondrial autophagy and inflammatory related differentially expressed genes (MIRDEGs) were used to construct a prognostic model in HNSCC. Through rigorous Kaplan–Meier curve analysis, we demonstrated the exceptional accuracy of our prognostic model over both 3- and 5-year intervals. DHRS2 knockdown suppressed cell proliferation, migration, and invasion in HNSCC, and enhanced apoptosis. Results: In total, 535 related genes were identified, and a 26-gene prognostic model was established, effectively stratifying patients into high- and low-risk groups (AUC: 0.7-0.9). DHRS2 was identified as a key gene of interest, with molecular docking indicating strong binding affinity to THD. in vitro, DHRS2 knockdown significantly inhibited HNSCC cell proliferation, migration, and invasion while promoting apoptosis (p<0.05). THD reduced DHRS2 expression and increased PINK1/Parkin-related mitophagy. Discussion: These findings suggest that dysregulation of mitophagy and inflammation contributes to HNSCC progression and may underlie radiation-induced inflammatory injury. DHRS2 was identified as a potential THD-responsive target, linking bioinformatics findings with pharmacological intervention. These findings also provide a basis for exploring therapeutic strategies targeting mitophagy and inflammation in HNSCC. Conclusion: We developed a prognostic model based on mitophagy- and inflammation-related genes in HNSCC and identified DHRS2 as a potential THD target. These results highlight the interplay between mitophagy and inflammation in HNSCC, offering insights for the prognosis and management of inflammation.