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. 2025 Aug 25.
doi: 10.1007/s13258-025-01667-2. Online ahead of print.

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

Jiao Ma #  1 , Huilin Zhang #  2 , Luanxue Yu  3 , Yunqing Guo  4 , Jiawei Ming  5 , Zhenying Guo  6   7
Affiliations

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

Jiao Ma et al. Genes Genomics. .

Abstract

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.

Keywords: CYTL1; H6PD; MR; Mesothelioma; Metabolism; scRNA-seq.

Plain language summary

Mesothelioma is a rare and aggressive cancer, often caused by asbestos exposure, with few treatment options and a poor prognosis. This study aims to find new ways to treat mesothelioma by identifying potential biomarkers and therapeutic targets.We used a multi-omics approach, which combines genetic, transcriptomic, and proteomic data, to explore the biology of mesothelioma. By looking at genetic variations, single-cell data, and protein analysis, we identified two important molecules—CYTL1 and H6PD—that play a key role in the cancer’s metabolism.Here’s what we found: CYTL1: This molecule is linked to a poor prognosis in mesothelioma patients. It also makes the cancer cells less responsive to certain drugs, suggesting it could be a potential target for new treatments. H6PD: This molecule seems to help mesothelioma grow by affecting the balance of certain sugars and amino acids in the cells. Despite not showing promising results in drug simulations, H6PD remains a candidate for further study. Our results show how understanding the metabolism of mesothelioma can lead to new treatment strategies. The findings highlight CYTL1 and H6PD as important targets that could guide future drug development for this challenging cancer.

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Conflict of interest statement

Declarations. Competing interests: None of the authors has a relevant competing interest. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable.

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