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Published on: October 31, 2025
Spatial transcriptomics and single-cell analysis reveal GSTO2-mediated protective networks in oral squamous cell
1Anhui Province Engineering Research Center for Dental Materials and Application, School of Stomatology, Wannan Medical College, Wuhu 241002, China; Department of Pathophysiology, Anhui Medical University, Hefei 230000, China.
Background:
Oral squamous cell carcinoma (OSCC) exhibits significant cellular heterogeneity and metabolic reprogramming that influence tumor progression and therapeutic responses. However, the molecular mechanisms underlying these processes remain poorly understood.
Methods:
We performed an integrated analysis of single-cell RNA sequencing and spatial transcriptomics analysis on OSCC samples to characterize cellular heterogeneity and identify key regulatory factors. Summary-data-based Mendelian randomization (SMR) analysis was conducted to establish causal links between gene expression and OSCC risk. Functional enrichment, protein-protein interaction (PPI) network analysis, molecular docking, and co-immunoprecipitation (Co-IP) were employed to elucidate molecular mechanisms.
Results:
Single-cell analysis of 50,667 cells identified nine distinct cell populations with epithelial cells showing the highest glutamine metabolism activity. SMR analysis revealed glutathione S-transferase omega 2 (GSTO2) as a genetically validated protective factor for OSCC risk. GSTO2-positive epithelial cells exhibited enhanced metabolic reprogramming, particularly in fatty acid degradation and amino acid catabolism pathways. Spatial transcriptomics demonstrated that GSTO2-positive cells were spatially organized and showed enhanced communication with immune cells. Protein-protein interaction analysis identified interferon-stimulated genes (MX1, OAS1, UBE2L6) and immunoproteasome subunits (PSMB8, PSMB9) as core regulatory hubs. Molecular docking confirmed direct binding interactions between GSTO2 and these hub proteins, with MX1-GSTO2 showing the strongest binding affinity (-10.7 kcal/mol). Co-immunoprecipitation experiments validated the physical interaction between GSTO2 and MX1.
Conclusions:
This study indicates that GSTO2 defines an epithelial subset characterized by enhanced metabolic activity and immune interactions, highlighting its potential as a biomarker and therapeutic target in OSCC.
Insights
Glutathione S-transferase omega 2 (GSTO2) protects against oral cancer by enhancing epithelial cell metabolism and immune interactions. This finding identifies GSTO2 as a potential biomarker and therapeutic target for oral squamous cell carcinoma (OSCC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Oral squamous cell carcinoma (OSCC) displays cellular heterogeneity and metabolic reprogramming impacting tumor progression.
- The precise molecular mechanisms driving these OSCC characteristics are not fully understood.
Purpose of the Study:
- To characterize OSCC cellular heterogeneity and identify key regulatory factors using integrated multi-omics analyses.
- To investigate the causal relationship between gene expression and OSCC risk.
- To elucidate the molecular mechanisms underlying OSCC progression and therapeutic response.
Main Methods:
- Integrated single-cell RNA sequencing and spatial transcriptomics on OSCC samples.
- Summary-data-based Mendelian randomization (SMR) analysis for gene expression-OSCC risk causality.
- Functional enrichment, protein-protein interaction (PPI) network analysis, molecular docking, and co-immunoprecipitation (Co-IP).
Main Results:
- Nine distinct cell populations were identified; epithelial cells showed high glutamine metabolism.
- Glutathione S-transferase omega 2 (GSTO2) was identified as a protective factor against OSCC risk.
- GSTO2-positive cells exhibited metabolic reprogramming and enhanced immune cell communication, interacting with interferon-stimulated genes and immunoproteasome subunits like MX1.
Conclusions:
- GSTO2 defines a specific epithelial cell subset in OSCC with heightened metabolic activity and immune interactions.
- GSTO2 demonstrates potential as a diagnostic biomarker and therapeutic target for OSCC.
- The study elucidates key molecular players and pathways involved in OSCC pathogenesis.
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