Bupleuri Radix ameliorates MASLD induced by high-fat diet and circadian disruption in rats: Involvement of the NR1D1–SREBF1/CYP7A1 circadian–metabolic axis

May 1, 2026Journal of ethnopharmacology

Bupleuri Radix improves fatty liver disease caused by high-fat diet and disrupted body clock in rats through the NR1D1 metabolic and circadian pathway

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Abstract

Bupleuri Radix (BR) fractions improved metabolic dysfunction-associated steatotic liver disease (MASLD) phenotypes in a rat model induced by a high-fat diet and circadian rhythm disruption.

BR fractions with different polarities exhibited varying degrees of protective effects against MASLD.
The BR-L fraction specifically regulated circadian hormone levels, particularly melatonin and cortisol.
Integration of multi-omics data indicated that BR-L altered glycerophospholipid metabolism and bile acid balance.
BR-L restored the rhythmic expression of Nr1d1 and synchronized the metabolic gene rhythms related to lipid and bile acid metabolism.
Nr1d1 was identified as a crucial link between circadian regulation and metabolic processes.

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ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to circadian rhythm disruption (CRD). While the biological clock coordinates metabolic homeostasis, the rhythmic signaling coupling lipid and bile acid metabolism remains unclear. Bupleuri Radix (BR; Bupleurum chinense DC.) is a traditional Chinese medicine widely used for liver-related disorders and known for its liver-soothing effect. However, whether its bioactive fractions can modulate the "circadian-metabolic coupling" process in MASLD has not yet been elucidated.

AIM OF THE STUDY: This study aimed to evaluate the protective effects of BR against high-fat diet (HFD)- and CRD-induced MASLD in rats and to explore its potential mechanisms through integrated multi-omics analysis.

MATERIALS AND METHODS: A rat model of MASLD was established by combining HFD feeding with CRD. Subsequently, BR fractions with different polarities were orally administered for 6 weeks. Biphenyldicarboxylate (BIC) and melatonin (MT) served as positive controls. Biochemical profiling, behavioral testing, histopathology, liver metabolomics, transcriptomics, and targeted bile acid analysis were performed. Diurnal gene expression was assessed at ZT05 and ZT17 by RT-qPCR.

RESULTS: Different polarity fractions of BR improved HFD + CRD-induced MASLD phenotypes to varying extents. Among them, BR-L showed more pronounced regulatory effects on circadian hormone disturbances, particularly MT and CORT. Multi-omics integration revealed that BR-L remodeled glycerophospholipid metabolism and bile acid homeostasis, centering on the Nr1d1-Srebf1-Cyp7a1 regulatory axis. BR-L restored the rhythmic oscillation of Nr1d1 and synchronized downstream lipid and bile acid metabolic gene rhythms. Correlation analysis further suggested Nr1d1 as a key node linking circadian and metabolic regulation.

CONCLUSION: The bioactive fractions of BR exert protective effects against HFD + CRD-induced MASLD. In particular, BR-L may act by restoring Nr1d1-associated rhythmic coordination of lipid and bile acid metabolism. This study provides a chronopharmacological perspective for the ethnopharmacological application of BR in metabolic liver diseases.

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Bupleuri Radix ameliorates MASLD induced by high-fat diet and circadian disruption in rats: Involvement of the NR1D1–SREBF1/CYP7A1 circadian–metabolic axis

Abstract

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