LL-37通过PTEN/AKT/mTOR通路抑制SQLE介导的胆固醇合成，从而抑制骨肉瘤进展
LL-37 inhibits osteosarcoma progression by suppressing SQLE-mediated cholesterol synthesis via the PTEN/AKT/mTOR pathway.
摘要(中文译文)
骨肉瘤（OS）是一种侵袭性原发性骨恶性肿瘤，转移性和复发性病例预后较差，凸显了对新型治疗策略的迫切需求。人源cathelicidin肽LL-37具有情境依赖性的抗肿瘤作用，但其在骨肉瘤中的功能作用在很大程度上仍不明确。本研究旨在探讨LL-37的抗骨肉瘤活性及其潜在机制。采用骨肉瘤细胞系和正常人骨髓间充质干细胞（hBMSCs）进行体外实验，评估细胞活力、克隆形成存活、迁移、侵袭、细胞周期分布、细胞死亡及胆固醇代谢。通过转录组分析、siRNA介导的基因敲低、质粒过表达及回补实验验证关键信号通路。采用143B细胞异种移植模型评估LL-37的体内治疗效果。LL-37选择性抑制骨肉瘤细胞的活力，对hBMSCs毒性极小。它显著抑制克隆形成存活、迁移和侵袭，诱导S期细胞周期阻滞，并触发线粒体凋亡和caspase-1/GSDMD依赖性焦亡。转录组分析确定胆固醇生物合成为LL-37下调的关键通路，限速酶角鲨烯环氧酶（SQLE）显著降低。机制上，LL-37上调抑癌基因PTEN，从而抑制AKT/mTOR通路并抑制SREBP2/SQLE介导的胆固醇合成。回补实验证实SQLE抑制是LL-37促凋亡作用所必需的。体内实验中，LL-37剂量依赖性抑制骨肉瘤异种移植物的生长，疗效与顺铂相当，且未引起明显的全身毒性。LL-37通过靶向PTEN/AKT/mTOR-SREBP2/SQLE轴抑制胆固醇合成并诱导双重细胞死亡，发挥抗骨肉瘤作用。它是一种有前景的选择性候选药物，为骨肉瘤胆固醇代谢靶向治疗提供了理论基础。
Abstract
Osteosarcoma (OS) is an aggressive primary bone malignancy with poor prognosis for metastatic and recurrent cases, highlighting an urgent need for novel therapeutic strategies. The human cathelicidin peptide LL-37 exerts context-dependent anti-tumor effects, yet its functional role in OS remains largely undefined. This study aimed to explore the anti-OS activity and underlying mechanisms of LL-37. In vitro experiments were performed using OS cell lines and normal human bone marrow mesenchymal stem cells (hBMSCs) to assess cell viability, clonogenic survival, migration, invasion, cell cycle distribution, cell death, and cholesterol metabolism. Transcriptomic profiling, siRNA-mediated knockdown, plasmid overexpression, and rescue experiments were conducted to validate key signaling pathways. The in vivo therapeutic efficacy of LL-37 was evaluated using a 143B cell xenograft model. LL-37 selectively inhibited the viability of OS cells with minimal toxicity to hBMSCs. It significantly suppressed clonogenic survival, migration, and invasion, induced S-phase cell cycle arrest, and triggered both mitochondrial apoptosis and caspase-1/GSDMD-dependent pyroptosis. Transcriptomic analysis identified cholesterol biosynthesis as a key pathway downregulated by LL-37, with the rate-limiting enzyme squalene epoxidase (SQLE) markedly reduced. Mechanistically, LL-37 upregulated the tumor suppressor PTEN, thereby inhibiting the AKT/mTOR pathway and suppressing SREBP2/SQLE-mediated cholesterol synthesis. Rescue experiments confirmed that SQLE inhibition was required for the pro-apoptotic effects of LL-37. In vivo, LL-37 dose-dependently inhibited the growth of OS xenografts with efficacy comparable to cisplatin, without causing obvious systemic toxicity. LL-37 exerts anti-OS effects by targeting the PTEN/AKT/mTOR-SREBP2/SQLE axis to suppress cholesterol synthesis and induce dual cell death. It represents a promising and selective candidate, providing a theoretical basis for cholesterol metabolism-targeted therapy in osteosarcoma.
如何引用
AMA
Fatai Lu, Zhijun Liu, Huasheng Jiang, Hong Zheng, Wenhui Su, Baosen Zhou. LL-37 inhibits osteosarcoma progression by suppressing SQLE-mediated cholesterol synthesis via the PTEN/AKT/mTOR pathway.. Journal of bone oncology. 2026; doi:10.1016/j.jbo.2026.100779.
APA
Fatai Lu, Zhijun Liu, Huasheng Jiang, Hong Zheng, Wenhui Su, Baosen Zhou (2026). LL-37 inhibits osteosarcoma progression by suppressing SQLE-mediated cholesterol synthesis via the PTEN/AKT/mTOR pathway.. Journal of bone oncology. https://doi.org/10.1016/j.jbo.2026.100779
GB/T 7714
Fatai Lu, Zhijun Liu, Huasheng Jiang, Hong Zheng, Wenhui Su, Baosen Zhou. LL-37 inhibits osteosarcoma progression by suppressing SQLE-mediated cholesterol synthesis via the PTEN/AKT/mTOR pathway.[J]. Journal of bone oncology, 2026 doi:10.1016/j.jbo.2026.100779.
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