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The high cost and attrition rate of drug development underscore the need for more effective strategies for therapeutic target discovery. Here, we present a network medicine-based machine learning framework that integrates single-cell transcriptomics, bulk multi-omic profiles, genome-wide CRISPR perturbation screens, and protein-protein interaction networks to systematically prioritise disease-specific targets. Applied to clear cell renal cell carcinoma, the framework successfully recovered established targets and predicted five therapeutic candidates, with subsequent in vitro validation demonstrating that among these, ENO2 inhibition had the strongest anti-tumour effect, followed by LRRK2, a repurposing candidate with phase III Parkinson's disease inhibitors. The proposed approach advances target discovery by moving beyond single-feature, single-modality heuristics to a scalable, machine learning-driven strategy that is generalisable across diseases.

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