骨肉瘤（OS）是一种高度致命的骨肿瘤，其特点是高恶性度和早期的肺转移。传统化疗对于提高OS患者的疗效和生存率无效。Butyrate（NaBu）被报道为一种新的抗肿瘤药物，可以抑制各种癌细胞的增殖和诱导凋亡。然而，NaBu对于骨肉瘤的铁死亡作用仍然不明确。本研究旨在调查NaBu是否促进了OS细胞中erastin诱导的铁死亡，并揭示其潜在机制。我们发现NaBu在体外显著增强了erastin诱导的铁死亡。与仅使用erastin的组相比，预处理NaBu加重了OS细胞中erastin介导的GSH耗竭、脂质过氧化和线粒体形态学改变。在皮下OS模型中，NaBu与erastin的联合应用显著抑制了肿瘤生长并增加了4-HNE的水平。机制上，NaBu通过调节ATF3表达下调了SLC7A11的转录。ATF3的过表达促进了erastin诱导铁死亡，而ATF3的沉默减弱了NaBu诱导的铁死亡敏感性。总之，我们的研究发现了NaBu在erastin诱导的铁死亡中的一个新角色，通过调节SLC7A11，表明NaBu可能是一种骨肉瘤治疗的潜在治疗药物。版权所有 © 2023. Elsevier B.V. 发表。

Osteosarcoma (OS) is a highly fatal bone tumor characterized by high degree of malignancy and early lung metastasis. Traditional chemotherapy fails in improving the efficacy and survival rate of patients with OS. Butyrate (NaBu) has been reported as a new antitumor drug for inhibiting proliferation and inducing apoptosis in various cancer cells. However, the effect of NaBu on the ferroptosis of osteosarcoma is still unknown. This study aimed to investigate whether NaBu promotes erastin-induced ferroptosis in OS cells and to uncover the underlying mechanism. Here, we found that NaBu significantly enhanced erastin-induced ferroptosis in vitro. Compared with the group that erastin used alonely, pre-treating with NaBu exacerbated erastin-meditated GSH depletion, lipid peroxidation, and mitochondrial morphologic changes in OS cells. In a subcutaneous OS model, NaBu combined with erastin significantly reduced tumor growth and increased the levels of 4-HNE. Mechanistically, NaBu downregulated SLC7A11 transcription via regulating ATF3 expression. Overexpression of ATF3 facilitated erastin to induce ferroptosis, while ATF3 knockdown attenuated NaBu-induced ferroptosis sensitivity. In conclusion, our findings revealed a previously unidentified role of NaBu in erastin-induced ferroptosis by regulating SLC7A11, suggesting that NaBu may be a potential therapeutic agent for OS treatment.Copyright © 2023. Published by Elsevier B.V.