Multi-omics integration reveals CYTL1 and H6PD as key regulators of tumor metabolism in mesothelioma.

Background: Mesothelioma is a rare and aggressive cancer with limited therapeutic options and poor prognosis. Despite advancements in understanding its molecular mechanisms, effective biomarkers and therapeutic targets remain elusive.

Objective: This study utilizes a multi-omics approach to identify potential biomarkers and therapeutic targets for mesothelioma.

Methods: A multi-omics framework integrating druggable genomics, Mendelian randomization (MR), and single-cell RNA sequencing (scRNA-seq) was employed. Druggable genes were identified using expression quantitative trait loci data, and therapeutic targets were predicted through MR analysis. These targets were cross-referenced with mesothelioma-specific single-cell markers and validated by summary data-based MR and protein quantitative trait loci analysis. Gene Ontology, KEGG, and Gene Set Enrichment Analysis were used to explore functional mechanisms. Drug sensitivity was assessed with the GDSC2 dataset, and potential therapeutic compounds were identified through molecular docking simulations using the Drug Signature Database. Mediated MR analysis investigated 731 immune cells and 1,400 metabolites as mediators of the identified genes' effects on mesothelioma.

Results: CYTL1 and H6PD were identified as potential biomarkers and therapeutic targets for mesothelioma. CYTL1 was associated with poor prognosis and reduced drug sensitivity, while H6PD showed the opposite trend. Although molecular docking results for H6PD were unfavorable, compounds targeting CYTL1 were identified. Immune cells did not mediate the effects of either gene on mesothelioma progression, despite their prognostic associations. Metabolic mediation analysis revealed that CYTL1 influences mesothelioma via levulinoylcarnitine levels, whereas H6PD regulates tumor metabolism through the mannose-to-mannitol-to-sorbitol ratio and glutamate-to-5-oxoproline ratio.

Conclusion: This study identifies CYTL1 and H6PD as key regulators of tumor metabolism in mesothelioma. CYTL1 is a promising therapeutic target, warranting further investigation, while H6PD remains a potential candidate despite unfavorable docking results. These findings demonstrate the value of multi-omics approaches in identifying novel therapeutic targets for mesothelioma.