Steamed Panax notoginseng saponins ameliorate cyclophosphamide-induced anemia by promoting erythroid progenitor proliferation via the cAMP/PI3K/AKT/cGMP pathway

  • J Ethnopharmacol. 2026 Nov 15:370:121971. doi: 10.1016/j.jep.2026.121971.
Cuiping Xu  1 ,  Hao Cui  2 ,  Qionglian Fang  2 ,  Hui Wang  1 ,  Pengfei Tu  3 ,  Xiuming Cui  4
Affiliations
  • 1. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China; Southwest United Graduate School, Kunming, 650500, China; Yunnan Key Laboratory of Panax Notoginseng, Kunming, 650500, China.
  • 2. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China; Yunnan Key Laboratory of Panax Notoginseng, Kunming, 650500, China.
  • 3. Southwest United Graduate School, Kunming, 650500, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: [email protected].
  • 4. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China; Southwest United Graduate School, Kunming, 650500, China; Yunnan Key Laboratory of Panax Notoginseng, Kunming, 650500, China; Laboratory of Sustainable Utilization of Panax Notoginseng Resources, State Administration of Traditional Chinese Medicine, Kunming, 650500, China. Electronic address: [email protected].
PMID: 42250832 DOI: 10.1016/j.jep.2026.121971
Abstract

Ethnopharmacological relevance: Steamed Panax notoginseng has long been used in traditional medicine to enrich the blood, and its principal constituents are saponins. This traditional blood-enriching property suggests its potential value in treating chemotherapy-induced anemia.

Aim of the study: To elucidate the underlying mechanism and identify the key active components through which steamed Panax notoginseng saponins (SPNS) ameliorate cyclophosphamide-induced anemia.

Materials and methods: A model of anemia was established by intraperitoneal injection of cyclophosphamide combined with acetylphenylhydrazine. Cell proliferation was evaluated by examining peripheral blood and HE-stained bone marrow sections. Our multiomics analysis revealed hematopoiesis-related pathways, and surface plasmon resonance (SPR) confirmed saponin binding to target proteins. The proliferative effect of individual saponins on erythrocytes was validated in zebrafish with fluorescently-labeled red blood cells. Cellular damage was assessed by flow cytometry and electron microscopy. The expression of hemoglobin-related genes and signaling pathway proteins was detected by Real-Time PCR and Western blotting, respectively.

Results: The cAMP and PI3K/Akt signaling pathways were significantly enriched in the SPNS group. The ginsenosides Rk3 and Rh4 were bound strongly to G protein-coupled receptors (GPCRs) and Guanylate Cyclase (GC), while F1 was bound to Integrin α5 (ITGA5). All three ginsenosides enhanced erythrocyte proliferation in zebrafish. SPNS also repaired cyclophosphamide (CTX)-induced damage in K-562 cells, promoted the expression of hemoglobin-related genes, and increased the phosphorylation of key proliferative pathway proteins.

Conclusions: SPNS mitigates cyclophosphamide-induced anemia by activating the cAMP/PI3K/Akt/cGMP pathway, an effect that is likely mediated by its active components Rk3, Rh4, and F1, thereby promoting erythropoiesis, inhibiting Apoptosis, and restoring hematopoietic function. This study provides valuable insights into clinical applications of the active ingredients of SPNS.

Keywords
Active ingredients; Anemia; Cell proliferation; Steamed Panax notoginseng saponins; cAMP/PI3K/AKT/cGMP signaling pathway.
Products