Estevez, S. R.; Baltusyte, G.; Youssef, G.; Han, N.

We present a generalisable, interpretable machine learning framework for therapeutic target discovery using single-cell transcriptomics, protein interaction networks, and drug proximity analysis. The pipeline integrates feature selection via gradient boosting classifiers, systems-level network inference, and in silico drug repurposing, enabling the identification of actionable targets with cellular specificity. As a proof of concept, we apply the method to clear cell renal cell carcinoma (ccRCC), an aggressive kidney cancer with limited treatment options. The model identifies 96 tumour-intrinsic genes, refines them to 16 targets through CRISPR screens and biological curation, and prioritises FDA-approved compounds via network-based proximity scoring. Several novel therapeutic mechanisms - including ABL1, CDK4/6, and JAK inhibition - emerge from this analysis, with predicted compounds showing superior efficacy to standard-of-care drugs across multiple ccRCC cell lines. Beyond ccRCC, this framework offers a scalable strategy for drug discovery across diverse diseases, combining machine learning interpretability with systems biology to accelerate therapeutic development.