Saikosaponin D, a triterpene saponin from Bupleurum falcatum, restores circadian rhythm and attenuates hepatic fibrosis via Esr1-Per2 axis.

Hepatic fibrosis, a precursor to chronic liver diseases, is linked to circadian rhythm disruptions. This study investigates the anti-fibrotic effects of saikosaponin D (SSd) from Bupleurum falcatum L. and its regulation of circadian genes. Transcriptomic and single-cell analyses revealed circadian gene dysregulation, particularly Period 2 (Per2), in liver fibrosis and hepatic stellate cells. SSd upregulated Per2 transcription via estrogen receptor 1 (Esr1), as confirmed by siRNA, real-time quantitative polymerase chain reaction, and Western blot analyses. In vivo, SSd alleviated fibrosis and hepatitis, increasing Esr1 but not Per2 protein levels. These findings suggest SSd exerts anti-fibrotic effects by modulating Esr1-mediated Per2 transcription.