Decoding multicomponent crosstalk: integrated pharmacodynamic‒pharmacokinetic network of sour jujube seed

Ziziphus jujuba var. spinosa seed (SJS) is a multicomponent traditional remedy with diverse pharmacological activities, including sedative, neuroprotective, anxiolytic, and cardiometabolic effects. However, identifying the bioactive constituents responsible for these broad therapeutic effects and understanding how they interact at the molecular level remains challenging due to the synergistic interactions among numerous phytochemicals. This review introduces an integrated pharmacodynamic-pharmacokinetic (PD-PK) network analysis to systematically decode the compound-target-pathway relationships of SJS. Pharmacokinetic profiling of key constituents (e.g., spinosin, jujuboside A and B) was combined with network pharmacology to map absorbed compounds to their biological targets and pathways. This approach revealed a holistic compound-target network, demonstrating that SJS's therapeutic efficacy arises from the synergistic effects of multiple constituents. These interacting compounds simultaneously modulate various targets and pathways, including neurotransmitter systems, inflammatory and antioxidant responses, and metabolic regulators. By incorporating PK constraints, non-bioavailable compounds were excluded, isolating core bioactive constituents and linking them to pharmacological actions within a rigorous, systems-level framework. The findings provide a comprehensive understanding of SJS's multifaceted mechanism of action, addressing previous knowledge gaps and highlighting how the integrated PD-PK paradigm can guide the rational development and clinical translation of SJS-based therapies.