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.

The tender leaves of Ziziphus jujuba var. spinosa (sour jujube) are widely consumed in China as a health-promoting tea, with triterpenoids being identified as one of their core bioactive constituents. However, key genes in the triterpenoid biosynthesis pathway remain largely uncharacterized in this species. Here, adenosine triphosphate (ATP) treatment inhibited sour jujube seedling growth, induced leaf curling and marginal withering in partial seedlings, and elevated triterpenoid content in seedling aboveground tissues. Transcriptome analysis showed that most mevalonic acid (MVA) pathway enzyme genes were not significantly altered, while some were downregulated, and some enzyme isoforms were slightly upregulated. Combined genome and transcriptome analysis identified one slightly upregulated oxidosqualene cyclase (OSC) gene, ZsLUS, among 13 sour jujube OSC family genes. Heterologous expression in yeast confirmed that ZsLUS encodes a bona fide lupeol synthase with catalytic activity. These results indicate that ATP treatment enhances triterpenoid accumulation without uniformly upregulating MVA pathway genes, suggesting a sub-pathway-specific regulatory mode or post-transcriptional regulatory mechanism for triterpenoid biosynthesis in sour jujube seedlings. This work deepens our understanding of the mechanism of ATP action on sour jujube triterpenoid biosynthesis and provides new clues for deciphering triterpenoid biosynthesis and accumulation in sour jujube leaves.