乳酰化驱动的代谢重编程通过HDGF介导的增殖和免疫调节促进骨肉瘤的恶性
Lactylation-driven metabolic reprogramming promotes osteosarcoma malignancy via HDGF-mediated proliferation and immune modulation.
摘要(中文译文)
骨肉瘤（OS）以显著的瘤内异质性和重塑的免疫微环境为特征。然而，代谢重编程驱动肿瘤进展的机制尚未被完全阐明。乳酸化修饰作为一种源自乳酸的表观遗传修饰，近年来已成为肿瘤代谢和免疫调节的关键调控因素。我们采用整合性多组学方法，结合单细胞RNA测序、空间转录组学和基于机器学习的预后建模，以解析骨肉瘤中乳酸化相关网络。通过共表达网络分析和SHapley加法解释（SHAP）可解释性框架识别关键驱动因子，随后进行实验性功能验证和潜在治疗药物的虚拟筛选。我们鉴定出一个具有高乳酸化活性、基因组不稳定性和干细胞样特性的独特肿瘤亚群，该亚群与患者不良预后相关。网络分析和SHAP分析确定肝癌衍生生长因子（HDGF）是该轴中的核心调控因子。功能研究表明，敲低HDGF可有效抑制骨肉瘤细胞增殖、迁移、侵袭和肿瘤生长。空间转录组学证实，升高的乳酸化活性与HDGF表达在肿瘤区域内共定位，将代谢重编程与局部微环境联系起来。此外，虚拟筛选鉴定出若干对HDGF具有高预测结合亲和力的FDA批准化合物。我们的研究揭示了一种促进骨肉瘤进展并调节肿瘤微环境的新型乳酸化-HDGF调控关联。这些发现凸显了HDGF作为有前景的预后生物标志物和治疗靶点的价值，为骨肉瘤的精准治疗提供了新途径。
Abstract
Osteosarcoma (OS) is characterized by significant intratumoral heterogeneity and a remodeled immune microenvironment. However, the mechanisms through which metabolic reprogramming drives tumor progression are not fully understood. Lactylation, an epigenetic modification derived from lactate, has recently emerged as a key regulator of tumor metabolism and immune modulation. We employed an integrative multi-omics approach, combining single-cell RNA sequencing, spatial transcriptomics, and machine learning-based prognostic modeling to decipher lactylation-associated networks in OS. Key drivers were identified through co-expression network analysis and SHapley Additive exPlanations (SHAP) interpretability frameworks, followed by experimental functional validation and virtual screening for potential therapeutics. We identified a distinct tumor subpopulation exhibiting high lactylation activity, genomic instability, and stem-like properties, which is associated with unfavorable patient prognosis. Network and SHAP analyses pinpointed hepatoma-derived growth factor (HDGF) as a central regulator within this axis. Functional studies demonstrated that HDGF knockdown potently inhibited OS cell proliferation, migration, invasion, and tumor growth . Spatial transcriptomics confirmed the colocalization of elevated lactylation activity and HDGF expression within tumor regions, linking metabolic reprogramming to the local microenvironment. Furthermore, virtual screening identified several FDA-approved compounds with high predicted binding affinity for HDGF. Our study unveils a novel lactylation-HDGF regulatory association that promotes OS progression and modulates the tumor microenvironment. These findings highlight HDGF as a promising prognostic biomarker and therapeutic target, offering new avenues for precision therapy in osteosarcoma.
如何引用
AMA
Shidong Hu, Ling Wu, Jianhua Wang, Fengsheng Dai. Lactylation-driven metabolic reprogramming promotes osteosarcoma malignancy via HDGF-mediated proliferation and immune modulation.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1836254.
APA
Shidong Hu, Ling Wu, Jianhua Wang, Fengsheng Dai (2026). Lactylation-driven metabolic reprogramming promotes osteosarcoma malignancy via HDGF-mediated proliferation and immune modulation.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1836254
GB/T 7714
Shidong Hu, Ling Wu, Jianhua Wang, Fengsheng Dai. Lactylation-driven metabolic reprogramming promotes osteosarcoma malignancy via HDGF-mediated proliferation and immune modulation.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1836254.
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