Liu Yun, Xie Tianyu, Liang Jiming, Feng Wenyu, Yang Mingxiu, Li Shanhang, Xiong Liang, Luo Kai, Li Feicui, Tang Shengping, Liu Shangyu, Huang Qian, Tang Haijun, Tang Fuxing, Wei Qingjun
Department of Spine and Bone disease, the First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, China.
Department of Traumatic Orthopaedic, the First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, China.
Phytomedicine. 2025 Jun 9;145:156960. doi: 10.1016/j.phymed.2025.156960.
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.
背景：骨肉瘤是一种起源于骨组织的罕见恶性肿瘤。尽管新辅助化疗取得了进展，但在过去五十年里，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性的出现。顺铂是当前治疗方案的基石，但在骨肉瘤患者中的反应率仍然较低，这凸显了提高顺铂敏感性策略的必要性。 目的：本研究旨在探讨生物活性化合物芒柄花素对骨肉瘤细胞对顺铂敏感性的影响。 研究设计：我们利用骨肉瘤的PDX模型来评估芒柄花素和顺铂的联合治疗效果。对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概况。 方法：建立骨肉瘤的PDX模型，然后用芒柄花素和顺铂进行治疗。共分析了7216个人源骨肉瘤细胞和89558个鼠源细胞，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：我们的研究结果表明，骨肉瘤中的顺铂不敏感性与铁死亡密切相关。芒柄花素通过抑制MAZ/GPX4轴并诱导铁死亡，使骨肉瘤细胞对顺铂敏感。此外，芒柄花素增加了NK细胞浸润和免疫活性，同时减少了耗竭的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并进一步提高顺铂敏感性。 结论：本研究首次证明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模型并进行全面的单细胞测序分析，我们确定芒柄花素是顺铂治疗的一种有前景的增敏剂。我们的研究结果提供了新的治疗见解和机制理解，有助于克服骨肉瘤中的顺铂不敏感性，并可能改善患者的预后。
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