2. Academic Validation
  3. Formononetin enhances cisplatin chemotherapy sensitivity in osteosarcoma by inducing ferroptosis and reconstructing the immune microenvironment

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

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: haijun2595@163.com.
  • 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: dontdrop@163.com.
  • 7 Department of Orthopaedic, the Second Affiliated Hospital of Guangxi Medical University, 530007, Nanning, China. Electronic address: weiqingjun@gxmu.edu.cn.
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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