Dual metabolic and mood-modulating effects of Schisandra chinensis lignans in hyperlipidemic rats: involvement of hepatic PPAR signaling and restoration of central GABAergic signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis (Turcz.) Baill., a traditional Chinese medicinal material documented in the Chinese Pharmacopoeia, has been used for centuries for tranquilizing and hepatoprotective purposes. Its dibenzocyclooctadiene lignans exhibit lipid-regulating properties, yet their peripheral-central integrative mechanisms remain incompletely understood.

AIM OF THE STUDY: To systematically evaluate S. chinensis lignans as a multi-targeted agent for hyperlipidemia and elucidate the coordinated peripheral-central mechanisms underlying their lipid-lowering and mood-modulating effects, providing scientific evidence for its ethnopharmacological use.

MATERIALS AND

METHODS

UPLC-Q-TOF-MS was employed for chemical characterization. A high-fat diet-induced hyperlipidemic rat model evaluated the effects of Schisandra lignans on metabolic parameters, inflammatory markers, histopathology, circadian rhythms, locomotor activity, and emotional behaviors. Network pharmacology, transcriptomics, molecular docking, Western blot, immunohistochemistry, and immunofluorescence were integrated.

RESULTS

Thirty-two dibenzocyclooctadiene lignans were identified. High-dose Schisandra lignans significantly ameliorated dyslipidemia, systemic inflammation, hepatic steatosis, and adipocyte hypertrophy; corrected disrupted metabolic circadian rhythms; restored locomotor activity; and alleviated anxiety- and depression-like behaviors. Integrated network pharmacology and transcriptomic analyses, together with protein-level validation, indicated the hepatic PPAR signaling pathway as a key peripheral mechanism, with upregulation of PPARα, CPT1A, and CYP7A1 and downregulation of HMGCR. Central GABAergic signaling in the ACC and PrL was restored.

CONCLUSIONS

These findings suggest that Schisandra lignans are a promising multi-targeted agent from a traditional Chinese medicinal material for hyperlipidemia management, with involvement of hepatic PPAR signaling and restoration of central GABAergic signaling, supporting its ethnopharmacological application for metabolic and emotional health.