Transcriptome-driven constraint-based modelling reveals metabolic targets for ovarian cancer.

Constraint-based modelling (CBM) is a powerful computational approach that reconstructs cellular metabolism by integrating ‘omics data with genome-scale metabolic models (GEMs), enabling in silico hypothesis generation and genetic engineering studies. Advances in high-throughput ‘omics technologies and the complete mapping of the human genome have expanded the application of CBM to human systems. Given that altered metabolism is a hallmark of cancer, this disease represents an ideal context for developing and applying CBM workflows. Despite the presence of well-characterised metabolic signatures and vulnerabilities in ovarian cancer, this tumour type remains under-explored within the CBM field. Meanwhile, the limited efficacy of current therapies and the frequent emergence of chemoresistance underscore the need for novel, mechanism-based approaches to therapeutic discovery. In this study, we constructed ovarian cancer-specific metabolic models using an ‘omics integration algorithm that incorporates transcriptomic data in a way that is directed by experimental proliferation measurements. Simulations identified multiple candidate molecules predicted to influence cancer cell proliferation. Among these, triosephosphate isomerase 1 (TPI1) was selected for experimental validation based on qualitative prioritisation criteria. Notably, model predictions were supported by RNA sequencing and colony-formation assays, implicating TPI1 in ovarian cancer cell survival. Our results provide novel insights into the metabolic dependencies of ovarian cancer and demonstrate an omics-integrated CBM workflow that may be broadly applicable for uncovering therapeutic vulnerabilities in other malignancies.