Zhang, Z.; Qiu, Z.; Wu, Y.; Li, S.; Wang, D.; Zhou, Z.; An, D.; Chen, Y.; Li, Y.; Wang, Y.; Ou, C.; Wang, Z.; Chen, J. X.; Zhang, B.; Hu, Y.; Zhang, W.; Wei, Z.; Ma, R.; Liu, Q.; Dong, B.; He, Y.; Feng, Q.; Bai, L.; Gao, Q.; Sun, S.; Zheng, S.

Therapeutic target discovery remains a critical yet intuition-driven bottleneck in drug development, typically relying on disease biologists to laboriously integrate diverse biomedical data into testable hypotheses for experimental validation. Here, we present OriGene, a self-evolving multi-agent system that functions as a virtual disease biologist, systematically identifying original and mechanistically grounded therapeutic targets at scale. OriGene coordinates specialized agents that reason over diverse modalities, including genetic data, protein networks, pharmacological profiles, clinical records, and literature evidence, to generate and prioritize target discovery hypotheses. Through a self-evolving framework, OriGene continuously integrates human and experimental feedback to iteratively refine its core thinking templates, tool composition, and analytical protocols, thereby enhancing both accuracy and adaptability over time. To comprehensively evaluate its performance, we established TRQA, a benchmark comprising over 1,900 expert-level question-answer pairs spanning a wide range of diseases and target classes. OriGene consistently outperforms human experts, leading research agents, and state-of-the-art large language models in accuracy, recall, and robustness, particularly under conditions of data sparsity or noise. Critically, OriGene nominated previously underexplored therapeutic targets for liver (GPR160) and colorectal cancer (ARG2), which demonstrated significant anti-tumor activity in patient-derived organoid and tumor fragment models mirroring human clinical exposures. These findings demonstrate OriGene\'s potential as a scalable and adaptive platform for AI-driven discovery of mechanistically grounded therapeutic targets, offering a new paradigm to accelerate drug development.