Xiaoyao San attenuates postmenopausal atherosclerosis via ERα-mediated suppression of hepatic PCSK9 transcription.

Authors

Yi Jing, Yanhong Yao, Qingping Xiong, Jun Yuan, Haijiang Zhang, Tianhui Hu

Published in

Phytomedicine : international journal of phytotherapy and phytopharmacology. Volume 159. Pages 158434. Jun 13, 2026. Epub Jun 13, 2026.

Abstract

Postmenopausal women exhibit elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, increasing atherosclerosis risk. Xiaoyao San (XYS), a classic herbal formula renowned for its ability to soothe the liver and relieve depression, is widely used in China to manage perimenopausal syndrome. Previous studies have found that it alleviates hepatic lipid accumulation through the Estrogen receptor α (ERα) signaling pathway, but its role in postmenopausal atherosclerosis via the PCSK9 regulatory mechanism remains unclear.
This study investigated XYS effects on delaying postmenopausal atherosclerosis by modulating hepatic PCSK9 transcription.
ApoE⁻/⁻ mice underwent bilateral ovariectomy and were fed a high-fat and high-fructose diet for 14 weeks to establish a postmenopausal atherosclerosis model. Using H&E staining, Oil Red O staining, Western blotting, and immunofluorescence, XYS reduced hepatic/serum PCSK9 and upregulated LDLR, attenuating dyslipidemia and atherosclerosis. Mechanistically, RNA-seq identified estrogen receptor signaling and the LXRα/SREBP-1c axis of fatty acid synthesis as the key molecular pathways. XYS upregulated ERα, suppressing LXRα/SREBP-1c-mediated hepatic steatosis and PCSK9 transcription. Consistent results were observed in insulin-treated cell models. Luciferase reporter assays demonstrated that XYS reduced sterol regulatory element (SRE)-dependent PCSK9 promoter activity. Notably, both in vivo targeted knockdown of hepatic ERα and in vitro treatment with the ERα antagonist ICI 182,780 reversed XYS-induced suppression of LXRα/SREBP-1c-mediated PCSK9 transcription, highlighting the critical role of hepatic ERα activation in XYS's inhibition of postmenopausal atherosclerosis progression.
XYS attenuates postmenopausal atherosclerosis by inhibiting hepatic PCSK9 transcription via ERα-mediated LXRα/SREBP-1c suppression, revealing a novel phytoestrogenic mechanism and potential as a natural PCSK9 inhibitor for cardiovascular protection.

PMID:
42320087
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.

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