Redefining post-stress depression as a spatiotemporal five-disease multimorbidity trajectory: ghrelin-driven anchoring by Shugan absorbed compounds

Aim: This study aimed to redefine post-stress depressive pathogenesis through a novel five-disease multimorbidity trajectory model (brain1-coronary-brain2-gastro-enteric; B1CB2GE) and to evaluate the multifunctional anchoring effects of Bupleurum chinense Shugan-San (BSS) and its absorbed compounds (ACs), including meranzin hydrate (MH), in AFS (acute forced swimming) male Sprague-Dawley rats. Methods: Temporal multimorbidity trajectories of B1CB2GE clusters were established in AFS rats and compared with single-disease models using 10 integrative analytic methods, including dynamic cluster trajectory modeling, biochemical profiling, and pharmacokinetic-pharmacodynamic (PK-PD) correlation analyses. A multi-cell experiment was used as a proxy for the in vivo system, whereas H-ECs (H2O2-treated endothelial cells) were used as a proxy for the multicellular system. Circulatory biomarkers related to oxidative, endothelial, and inflammatory (OEI) impairment, brain-derived neurotrophic factor (BDNF) levels, and cecal butyrate contents were measured. The role of the ghrelin (Ghr) receptor was examined using the antagonist D-Lys3-GHRP-6 (D-Lys). Forced-swim test, gastric emptying, enteric transit, and coronary flow were used to characterize post-AFS multimorbidity trajectory phenotypes in animals. Results: Fifteen minutes after AFS, distinct temporal B1CB2GE multimorbidity clusters emerged with normalized ranking values: G 15.31 > B2 1.17 > B1 0.85 > C 0.49 > E 0.32. These clusters were accurately anchored by BSS and its five tailored sets of 1–10 ACs, demonstrating multifunctional modulation ranging from 53.23% to 156.32%, with optimal anchoring efficiency of 96.37–104.14%. MH, a representative multifunctional compound, exhibited the strongest prokinetic and OEI-restorative effects, elevating BDNF and cecal butyrate levels. These therapeutic effects were abolished by D-Lys, confirming a Ghr-dependent mechanism. Conclusions: This study introduces a multimorbidity trajectory framework (B1CB2GE) for modeling post-stress depression and demonstrates that Shugan-like herbal formulas such as BSS effectively anchor dynamic multimorbidity progression via multifunctional compounds like MH. These findings provide a systems-pharmacology basis for understanding and treating complex comorbid depressive disorders through multifunctional anchoring herbal therapeutics.