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

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.

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).

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.

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.

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.