Available online 28 June 2025

The development of resistance to CDK4/6 inhibitors is a significant challenge in treating estrogen receptor-positive (ER+) breast cancer. This study aimed to explore the regulatory mechanisms of ginsenoside Rg5 in enhancing Abemaciclib sensitivity in ER+ breast cancer.

Abemaciclib-resistant ER+ breast cancer cell lines were established. Cell viability, colony formation, cell cycle progression, and apoptosis were evaluated following treatment with ginsenoside Rg5 and/or Abemaciclib. Molecular mechanisms were investigated using Western blot analysis, qRT-PCR, co-immunoprecipitation, and cycloheximide chase assays. The therapeutic efficacy of ginsenoside Rg5 was further validated in xenograft models.

Ginsenoside Rg5 significantly enhanced Abemaciclib sensitivity in both parental and resistant ER+ breast cancer cells. The combination treatment induced G1 arrest and apoptosis more effectively than either agent alone. Mechanistically, Rg5 suppressed the PI3K/Akt signaling pathway, downregulated CDK4 and CDK6 mRNA expression, and disrupted the HSP90-CDC37 chaperone complex. This disruption promoted proteasomal degradation of CDK2, CDK4, and CDK6 proteins. Introduction of an HSP90α-Y61A mutant, which resists Rg5 binding, abrogated these effects both in vitro and in vivo.

Ginsenoside Rg5 increases the sensitivity of ER+ breast cancer cells by modulating cell cycle proteins via transcriptional and post-translational levels. These findings provide insights into novel combination therapies to circumvent CDK4/6 inhibitor resistance in ER+ breast cancer.

ginsenoside Rg5

HSP90

CDK4/6 inhibitors

ER+ breast cancer

© 2025 The Korean Society of Ginseng. Publishing services by Elsevier B.V.