Recent advances in the target identification strategies of natural products: an overview from 2014 to 2025

Natural products (NPs) are indispensable in drug discovery. Their complex structure, diverse functions, and natural biological compatibility enable potent interactions with cellular macromolecules. Unlike synthetic drugs specifically designed to target therapeutic molecules with well-defined mechanisms of action, the discovery of NPs usually involves exploring natural sources, isolating active compounds, and validating their efficacy. As a result, the precise molecular targets and pharmacological mechanisms of NPs often remain unclear. Additionally, the intrinsic properties of NPs, such as structural lability, low bioavailability, and activity at sub-micromolar concentrations, limit the effectiveness of conventional target identification approaches. Over the past decade (2014–2025), pharmacological research on NPs has shifted toward identifying their direct targets, with significant progress made in chemicobiological, biophysical, and computational techniques. In this review, recent advances in target identification of NPs are summarized, with attention to methodologies that leverage protein libraries, in-situ models, and emerging technologies like bioinformatics. Future directions are also proposed to accelerate NP-based drug development through more efficient, targeted identification.