2. Academic Validation
  3. Concentrated Angelica sinensis pills ameliorate ovarian insufficiency by promoting vascular remodeling via inhibiting CYP1B1/ACSL4-mediated ferroptosis

Concentrated Angelica sinensis pills ameliorate ovarian insufficiency by promoting vascular remodeling via inhibiting CYP1B1/ACSL4-mediated ferroptosis

  • Phytomedicine. 2026 May:154:158024. doi: 10.1016/j.phymed.2026.158024.
Chen Ling 1,  Xiaodan Liu 1,  Lu Liu 1,  Liang Hui 2,  Jin Pu 2,  Li Yang 2,  Xueyun Liang 1,  Haibin Ma 1,  Huiming Ma 3,  Dongmei Chen 4
Affiliations

Affiliations

  • 1 Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, No. 804 Shengli Street, Xingqing District, Yinchuan, China.
  • 2 Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Animal Experiment Center, Ningxia Medical University, Yinchuan, China.
  • 3 Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Animal Experiment Center, Ningxia Medical University, Yinchuan, China. Electronic address: [email protected].
  • 4 Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, No. 804 Shengli Street, Xingqing District, Yinchuan, China. Electronic address: [email protected].
PMID: 41795290 DOI: 10.1016/j.phymed.2026.158024
Abstract

Background: Ferroptosis in ovarian vascular endothelial cells contributes to the pathogenesis of premature ovarian insufficiency (POI). Concentrated Angelica sinensis pill (Ang), a traditional Chinese medicine renowned for tonifying Qi and nourishing blood, exhibits ovary-protective properties. However, whether Ang ameliorates POI by suppressing endothelial Ferroptosis and the underlying molecular mechanisms remains to be elucidated.

Purpose: To investigate whether Ang improves POI by promoting ovarian angiogenesis via the inhibition of endothelial Ferroptosis, and to characterize its regulation of lipid peroxidation and the CYP1B1/ACSL4 signaling axis.

Methods: POI was induced in female Sprague-Dawley rats via 4-vinylcyclohexene diepoxide administration. Rats received Ang or ferrostatin-1, a Ferroptosis inhibitor, as interventions. The therapeutic mechanisms were explored using an integrated multi-omics approach comprising high-throughput RNA Sequencing, LC-MS-based metabolomics/lipidomics, and network pharmacology. Key molecular targets and pathways were validated through histological analyses, biochemical assays, and in vitro experiments using human umbilical vein endothelial cells.

Results: Ang treatment significantly restored ovarian function in POI rats, evidenced by improved estrous cyclicity, hormonal profiles, folliculogenesis, and increased ovarian angiogenesis. Transcriptomic profiling and network pharmacology identified Ferroptosis, lipid metabolism, and angiogenesis as key therapeutic pathways, highlighting CYP1B1, ACSL4, and GPX4 as critical targets. Metabolomic and lipidomic analyses revealed that Ang mitigated oxidative stress by limiting the oxidation of polyunsaturated fatty acids, thereby rebalancing arachidonic acid and phospholipid metabolism. Mechanistically, Ang upregulated CYP1B1 and downregulated ACSL4 in vitro. Furthermore, Ang effectively suppressed lipid peroxidation, indicated by reduced ROS, MDA, and Liperfluo intensity, and restored the angiogenic capacity of endothelial cells, mirroring the effects of Fer-1.

Conclusion: Ang ameliorates ovarian insufficiency by promoting ovarian angiogenesis by inhibiting endothelial Ferroptosis. This protective effect is likely mediated by the regulation of lipid peroxidation and the CYP1B1/ACSL4 axis, offering a novel therapeutic strategy for POI.

Keywords

Angiogenesis; CYP1B1/ACSL4 axis; Endothelial cells; Ferroptosis; Lipid metabolism; Premature ovarian insufficiency.

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