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

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-09 DOI:10.1016/j.phymed.2025.156960

Yun Liu , Tianyu Xie , Jiming Liang , Wenyu Feng , Mingxiu Yang , Shanhang Li , Liang Xiong , Kai Luo , Feicui Li , Shengping Tang , Shangyu Liu , Qian Huang , Haijun Tang , Fuxing Tang , Qingjun Wei

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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.

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刺芒柄花素通过诱导铁下垂和重建免疫微环境增强骨肉瘤顺铂化疗敏感性

背景：骨肉瘤是一种罕见的起源于骨组织的恶性肿瘤。尽管新辅助化疗取得了进步，但在过去的50年里，骨肉瘤患者的5年生存率一直稳定在60%左右，这主要是由于化疗不敏感的发展。顺铂作为目前治疗方案的基石，在骨肉瘤患者中仍有较低的应答率，这突出了提高顺铂敏感性的策略的必要性。目的探讨刺芒柄花素（一种生物活性化合物）对骨肉瘤细胞顺铂敏感性的影响。研究设计采用骨肉瘤PDX模型，评价刺芒柄花素与顺铂联合治疗骨肉瘤的疗效。对来自这些模型的肿瘤组织进行单细胞RNA测序和单细胞ATAC测序，以提供治疗效果的详细分子图谱。方法建立骨肉瘤spdx模型，给予刺芒柄花素和顺铂治疗。共分析了7216个人源性骨肉瘤细胞和89,558个小鼠源性骨肉瘤细胞，以评估它们在顺铂敏感性和肿瘤免疫微环境变化中的作用。结果骨肉瘤患者顺铂不敏感与铁下垂密切相关。刺芒柄花素通过抑制MAZ/GPX4轴和诱导铁下垂使骨肉瘤细胞对顺铂敏感。此外，刺芒柄花素增加NK细胞的浸润和免疫活性，同时减少耗尽的Cd8+ T细胞和肿瘤相关中性粒细胞的浸润，从而重新编程肿瘤免疫微环境，进一步增强顺铂敏感性。结论本研究首次证实刺芒柄花素可增强骨肉瘤对顺铂的敏感性。通过使用骨肉瘤PDX模型和进行全面的单细胞测序分析，我们确定刺芒柄花素是一种有希望的顺铂治疗增敏剂。我们的研究结果提供了新的治疗见解和机制理解，可以帮助克服骨肉瘤的顺铂不敏感，并有可能改善患者的预后。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.