Unveiling Dragon’s Blood Radiation Mitigation Mechanism: Identifying Key Targets and Bioactive Compounds with Multiomics Using Integrated AI-Driven Models

Radiotherapy often causes severe and irreversible neural damage, including cognitive impairment and depression-like behaviors. Current mitigants are limited, with single-target molecules being ineffective and nanomedicines posing complexity and toxicity risks. Dragon’s Blood (DB), a nontoxic, brown-red resin extracted from Dracaena cochinchinensis (Lour.) (S. C. Chen, China), possesses diverse pharmacological properties. Extensive studies demonstrated that the compounds in DB exhibit multiple therapeutic effects, including cardiovascular protection, promotion of blood circulation, and anti-inflammatory effect. Herein, DB’s neuronal radiation mitigation effect and mechanism were investigated. In a whole-brain irradiation rat model, DB administration significantly alleviated radiation-induced anhedonia-like behavior, normalized calcium dyshomeostasis, restored mitochondrial membrane potential, mitigated dendritic spine loss, suppressed neuroinflammation (IL-1β and TNF-α), and preserved hippocampal cytoarchitecture. Brain tissue proteomics revealed 23 DB-modulated KEGG pathways, encompassing the glutamatergic/GABAergic synapse, synaptic plasticity, addiction-related pathways, calcium/cAMP signaling, and hormonal regulation. Ensemble analysis integrating proteomics, WGCNA, machine learning, and PPI pinpointed 24 DB radiation mitigation-related proteins. Among these, eight targets (Grin1, Gabra4, Grm2, Grm3, Grm7, Prkcb, Shank3, and Pak7) functioning via ligand–target interactions were dysregulated by radiation and restored by DB. Molecular docking identified three DB ingredients (socotrin-4′-ol, cinnabarone, and 2′-methoxysocotrin-5′-ol) interacted with all eight targets. Plasma proteomics further revealed radiation mitigation-related brain-enriched proteins (Mib1, Gucy1b1, Fkbp1a, Synj1, and Clasp2). PPI between these 5 plasma proteins and 24 brain proteins reveals DB’s multitarget radiation mitigation effect on neurotransmission and synaptic regulation, neuroplasticity, and signaling transduction and cellular response. This work nominated DB and its key constituents as promising candidates for mitigating radiotherapy-induced neural injury.