Spatial Pharmacology Reveals Where Natural Products Act Across Tissues, Niches, Microenvironments, Disease Compartments

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Natural-product pharmacology is usually interpreted through concentrations, targets, pathways, and phenotypes, yet each of these can vary across physical space. Plasma exposure or whole-tissue abundance may therefore coexist with markedly different concentrations across anatomical compartments, cellular neighborhoods, barrier environments, and metabolically distinct regions. This article develops an original conceptual framework for treating spatial location as an explicit coordinate of pharmacological inference. The framework separates four questions that are frequently conflated: where a compound or locally formed species is detected, whether pharmacologically relevant exposure is achieved at that location, whether a target or susceptible cellular state is available there, and whether a local response is observed. Spatial mass spectrometry imaging, spatial metabolomics, transcriptomics, proteomics, and multiplexed tissue imaging provide complementary evidence for these questions, but no single modality establishes site of action. Natural-product examples further show that formulation, tissue architecture, local metabolism, and disease microenvironment can reshape what reaches a region and what molecular response is subsequently measured. The proposed Location–Exposure–Target–Response framework therefore treats spatial mechanism as a convergence problem rather than a colocalization problem. It also distinguishes accumulation from action and requires uncertainty in molecular identity, quantitation, resolution, and registration to remain visible during interpretation. The framework is intended as an evidence-organizing and hypothesis-generating structure, not a validated predictor of efficacy, toxicity, or clinical tissue selectivity. Prospective testing should determine whether this structured convergence improves pharmacological interpretation or lead prioritization.