Multi-omics profiling of ACOX3 unveils pan-cancer clinical biomarker potential

This study aims to comprehensively characterize ACOX3 as a novel pan-cancer biomarker by assessing its expression heterogeneity, clinical relevance, tumor-immune interactions and therapeutic potential across multiple cancer types.

The multi-omics analyses of the ACOX3 expression pattern were performed. Prognostic and diagnostic significance was evaluated by Cox regression, Kaplan-Meier survival and ROC analyses. Immune correlates were assessed in terms of immune cell infiltration, checkpoint and immunomodulatory activity. Drug sensitivity was predicted through molecular docking and molecular dynamics simulations to evaluate binding affinity and complex stability. Experimental validation was conducted in HNSCC cell lines.

ACOX3 was significantly upregulated in KICH, PRAD and THCA, and downregulated in COAD, HNSCC, KIRP, LIHC and STAD. The OS Cox regression showed high ACOX3 expression was associated with a favorable prognosis in HNSCC but poor outcomes in LGG and UVM. The ROC curves showed that the AUC for ESCA, GBM, OV, PAAD, STES and WT exceeded 0.8. ACOX3 expression positively correlated with CD4⁺T, CD8⁺T and NK cells in HNSCC. Single-cell and spatial transcriptomics revealed ACOX3 enrichment in malignant regions, particularly in CD4⁺T, CD8⁺T and CD8⁺Tex cells. Drug screening prioritized AZD6482 and TGX-221 as high-affinity ACOX3 inhibitors, and the AZD6482 showed stable binding in MD simulations. Functional experiments confirmed that ACOX3 overexpression suppressed HNSCC cell proliferation, invasion and migration.

ACOX3 represents a dual diagnostic and prognostic biomarker with broad pan-cancer relevance, exhibiting distinct immune correlates and therapeutic potential.