铁死亡是一种独特的细胞死亡类型，其特点是依赖铁依赖性和脂质过氧化（LPO）。因此，小分子铁死亡调节剂作为癌症治疗的一种有前景的途径引起了人们的极大兴趣。在此，我们探讨了表观遗传调节剂的铁死亡敏感性，发现 I 类组蛋白脱乙酰酶 (HDAC) 抑制剂的抗增殖作用显着依赖于铁死亡。随后，我们开发了一系列新型 HDAC 抑制剂，鉴定出 HL-5 对 I 类 HDAC，特别是 HDAC1 具有强大的抑制活性。值得注意的是，HL-5s 通过增加 LPO 的产生来诱导铁死亡。从机制上讲，HL-5s 增加 YB-1 乙酰化并抑制 Nrf2/HO-1 信号通路。此外，HL-5s不仅显着抑制PC-9异种移植模型中的肿瘤生长，而且还重塑了LLC同种异体移植模型中的肿瘤微环境。我们的研究表明，I 类 HDAC 抑制剂可以通过引发铁死亡来发挥抗肿瘤作用，而 HL-5 可能成为未来癌症治疗的有希望的候选者。

Ferroptosis is a unique type of cell death, characterized by its reliance on iron dependency and lipid peroxidation (LPO). Consequently, small-molecule ferroptosis modulators have garnered substantial interest as a promising avenue for cancer therapy. Herein, we explored the ferroptosis sensitivity of epigenetic modulators and found that the antiproliferative effects of class I histone deacetylase (HDAC) inhibitors are significantly reliant on ferroptosis. Subsequently, we developed a novel series of HDAC inhibitors, identifying HL-5s with robust inhibitory activity against class I HDACs, particularly HDAC1. Notably, HL-5s induces ferroptosis by augmenting LPO production. Mechanistically, HL-5s increased the YB-1 acetylation and inhibited the Nrf2/HO-1 signaling pathway. Furthermore, HL-5s not only significantly suppresses tumor growth in the PC-9 xenograft model but also remodels the tumor microenvironment in the LLC allograft model. Our study has unveiled that class I HDAC inhibitors can exert antitumor effects by triggering ferroptosis, and HL-5s may serve as a promising candidate for future cancer treatment.