Oral squamous cell carcinoma (OSCC) is a malignant tumor characterized by both clinical and molecular heterogeneity. Its rising global incidence and mortality rates pose considerable clinical challenges. Accumulating evidence suggests that dysregulation of mitochondria-associated pan-cell death, a process integrating multiple mitochondrial-related cell death modalities, is closely linked to tumor initiation and progression. Nevertheless, the identification of key therapeutic targets among mitochondria-associated pan-cell death-related genes (MAPGs) in OSCC remains an unresolved issue, underscoring the need for further investigation. We systematically investigated the expression patterns, prognostic relevance, and immune microenvironmental features of mitochondria-associated pan-cell death-related genes (MAPGs) in OSCC by integrating data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets (GSE42743, GSE41613, GSE75538, GSE164241, GSE172577, and GSM6339633), and the MitoCarta3.0 database. Using nine machine learning algorithms, we compared the importance and prognostic value of MAPGs and identified INHBA as the most pivotal MAPG. Its predictive power and functional relevance were further explored through enrichment analysis. We validated INHBA mRNA expression levels in clinical OSCC samples using quantitative real-time PCR (qRT‑PCR). Pan-cancer analysis was performed to assess the potential of INHBA as a therapeutic target across multiple cancer types. Single-cell RNA sequencing, spatial transcriptomics, and cell-cell communication analyses were integrated to elucidate the spatial distribution of INHBA in OSCC and its crosstalk with the immune microenvironment. Finally, drug sensitivity profiling was conducted using the GDSC and PRISM databases. A total of 19 MAPGs with the greatest prognostic value were screened out. Among them, INHBA emerged as the most critical MAPG, which was overexpressed in HNSCC and strongly correlated with poor prognosis in OSCC patients (p < 0.05). Meanwhile, INHBA expression was elevated in cancer-associated fibroblasts (CAFs). Spatial transcriptomic analysis further revealed strong spatial colocalization between INHBA and CAF-localized regions. These results indicated that INHBA primarily functioned within CAFs, especially myCAFs, and may promote OSCC progression through modulation of the immune microenvironment. Elevated INHBA expression served as a prognostic indicator in OSCC, a finding consistent with its prognostic relevance in broader HNSCC analyses. Selumetinib and naltrexone showed high sensitivity in INHBA-high contexts. INHBA is a crucial MAPG that is upregulated in OSCC and mainly functions in CAFs. It likely affects the poor prognosis of OSCC by regulating the immune microenvironment. Selumetinib and naltrexone hold promise as innovative therapeutic agents, potentially opening up new treatment avenues for OSCC patients.
Zhang et al. (Wed,) studied this question.