Formononetin enhances cisplatin chemotherapy sensitivity in osteosarcoma by inducing ferroptosis and reconstructing the immune microenvironment

  • Phytomedicine. 2025 Jun 9:145:156960. doi: 10.1016/j.phymed.2025.156960.
Yun Liu  1 ,  Tianyu Xie  2 ,  Jiming Liang  1 ,  Wenyu Feng  3 ,  Mingxiu Yang  1 ,  Shanhang Li  4 ,  Liang Xiong  2 ,  Kai Luo  1 ,  Feicui Li  1 ,  Shengping Tang  2 ,  Shangyu Liu  1 ,  Qian Huang  2 ,  Haijun Tang  5 ,  Fuxing Tang  6 ,  Qingjun Wei  7
Affiliations
  • 1. Department of Spine and Bone disease, the First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, China.
  • 2. Department of Traumatic Orthopaedic, the First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, China.
  • 3. Department of Orthopaedic, the Second Affiliated Hospital of Guangxi Medical University, 530007, Nanning, China.
  • 4. Department of Bone and Soft Tissue, the Affiliated Tumour Hospital of Guangxi Medical University, 530021, Nanning, China.
  • 5. Department of Spine and Bone disease, the First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, China. Electronic address: [email protected].
  • 6. Department of Spine and Bone disease, the First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, China; Department of Minimally Invasive Spinal Surgery, Yulin Orthopedics Hospital of Chinese and Western Medicine, 537000, Yulin, Guangxi, China. Electronic address: [email protected].
  • 7. Department of Orthopaedic, the Second Affiliated Hospital of Guangxi Medical University, 530007, Nanning, China. Electronic address: [email protected].
PMID: 40543234 DOI: 10.1016/j.phymed.2025.156960
Abstract

Background: Osteosarcoma is a rare malignant tumor originating from bone tissue. Despite advancements in neoadjuvant chemotherapy, the 5-year survival rate for osteosarcoma patients has plateaued around 60 % for the past fifty years, primarily due to the development of chemo-insensitivity. Cisplatin, a cornerstone in current treatment regimens, still has a low response rate in osteosarcoma patients, highlighting the need for strategies to enhance cisplatin sensitivity.

Purpose: The purpose of this study is to explore the effects of formononetin, a bioactive compound, in sensitizing osteosarcoma cells to cisplatin.

Study design: We utilized PDX models of osteosarcoma to evaluate the combined therapeutic effect of formononetin and cisplatin. Single-cell RNA Sequencing and single-cell ATAC Sequencing were performed on tumor tissues from these models to provide a detailed molecular profile of the treatment effects.

Methods: PDX models of osteosarcoma were established, followed by treatment with formononetin and cisplatin. A total of 7216 human-derived osteosarcoma cells and 89,558 mouse-derived cells were analyzed to assess their role in cisplatin sensitivity and tumor immune microenvironment changes.

Results: Our findings demonstrated that cisplatin insensitivity in osteosarcoma is strongly linked to Ferroptosis. Formononetin sensitized osteosarcoma cells to cisplatin by inhibiting MAZ/GPX4 axis and inducing Ferroptosis. Additionally, formononetin increased NK cell infiltration and immune activity, while reducing the infiltration of exhausted Cd8+ T cells and tumor-associated neutrophils, thereby reprogramming the tumor immune microenvironment and further enhancing cisplatin sensitivity.

Conclusion: This study is the first to demonstrate that formononetin can enhance cisplatin sensitivity in osteosarcoma. By using osteosarcoma PDX models and performing comprehensive single-cell Sequencing analyses, we identified formononetin as a promising sensitizer for cisplatin treatment. Our findings offer new therapeutic insights and mechanistic understanding that could help overcome cisplatin insensitivity in osteosarcoma and potentially improve patient outcomes.

Keywords
Cisplatin; Ferroptosis; Formononetin; MAZ/GPX4; Osteosarcoma.
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