MARCH8/NSUN6/ROS-mediated DNA damage positive feedback loop regulates cisplatin resistance in osteosarcoma.

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Abstract

[Indexed for MEDLINE] Conflict of interest statement: Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: Ethical approval for the study was granted by the Harbin Medical University Animal Ethical committee, in accordance with the principles of the Declaration of Helsinki. 16. Cell Death Dis. 2025 Oct 7;16(1):712. doi: 10.1038/s41419-025-08037-6. HMGB1 orchestrates tumor-osteoclast crosstalk to drive bone metastasis in hepatocellular carcinoma. Chen YZ(1), Xu D(1), Jia YX(1), Ma J(1), Xiang ZL(2)(3). Author information: (1)Department of Radiation Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. (2)Department of Radiation Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. xiangzuolinmd@hotmail.com. (3)Department of Radiation Oncology, Shanghai East Hospital Ji'an Hospital (Ji'an Central People's Hospital), Ji'an, China. xiangzuolinmd@hotmail.com. Bone metastasis in hepatocellular carcinoma (HCC) poses a significant clinical challenge, characterized by poor prognosis and severe skeletal complications. This study identifies the HMGB1/LCN2/JAK1/STAT3 axis as the central mechanism driving HCC bone metastasis through tumor-osteoclast crosstalk. High-mobility group box 1 (HMGB1) induces osteoclast activation and differentiation, promoting lipocalin-2 (LCN2) secretion by osteoclasts, which activates the JAK1/STAT3 pathway in HCC cells, forming a feedback loop that enhances osteolytic bone resorption and tumor dissemination. Integrated single-cell and bulk RNA sequencing reveal enriched osteoclast-related and pro-metastatic pathways in the tumor-bone microenvironment, while functional assays involving knockdown and overexpression demonstrate that modulating the HMGB1/LCN2/JAK1/STAT3 axis regulates osteoclast activity, tumor growth, and bone destruction in vitro and in vivo. These results suggest the HMGB1/LCN2/JAK1/STAT3 axis as a potential therapeutic target, offering a strategy to reduce skeletal damage and systemic tumor progression, thereby contributing to improved management of advanced HCC. © 2025. The Author(s). DOI: 10.1038/s41419-025-08037-6 PMCID: PMC12504543