Phosphoproteomics and Multi-Omics for Oleanolic Acid Target Deconvolution: From Phosphorylation Signatures to Mechanistic Validation

Oleanolic acid (OA) is a pentacyclic triterpenoid with broad biological activity, but its primary molecular points of engagement remain incompletely resolved. Most available studies describe OA through selected pathway markers, particularly within PI3K/AKT/mTOR, AMPK/mTOR, MAPK, NF-κB, and Nrf2 signaling, without clearly distinguishing direct target engagement from downstream adaptive responses. This limits mechanistic interpretation and weakens translational prioritization. This review focuses specifically on phosphoproteomics-centered and multi-omics-assisted target deconvolution of OA rather than providing a comprehensive catalog of all reported biological effects of OA. We examine why phosphoproteomics is particularly informative for capturing early signaling events, how it can be integrated with total proteomics, transcriptomics, metabolomics, and chemoproteomic approaches, and why orthogonal target-engagement methods remain essential for stronger causal inference. We also organize the current signaling evidence for OA and its derivatives, distinguishing pathway association, kinase/phosphatase activity inference, target prioritization, and direct target validation. The strongest mechanistic support for the parent compound currently concerns AMPK/mTOR-linked regulation of autophagy and apoptosis, whereas evidence for several other pathways remains more heterogeneous, derivative-dependent, or marker-based. Finally, we propose a stepwise workflow for OA target deconvolution based on time-resolved phosphoproteomics, informative phosphosite subsets, multi-omics integration, kinase/phosphatase activity inference, and experimental target validation. This framework may help move OA research from descriptive pathway pharmacology toward mechanism-based target prioritization and more rational derivative development.