Yang Zhou, Su Wei, Zhang Qinglin, Niu Lili, Feng Baijie, Zhang Yu, Huang Feng, He Jiaxin, Zhou Qinyao, Zhou Xin, Ma Longjun, Zhou Jingwan, Wang Yuanrong, Xiong Wenjing, Xiang Jun, Hu Zhilin, Zhan Qiang, Yao Bing
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Adv Sci (Weinh). 2025 Mar;12(12):e2408845. doi: 10.1002/advs.202408845. Epub 2025 Jan 31.
Colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the application of anti-ferroptosis therapy. Through drug screening, it is found that histone deacetylase inhibitor (HDACi) significantly sensitized CRC to ferroptosis. The combination of HDACi and ferroptosis inducers synergically suppresses CRC growth both in vivo and in vitro. Mechanically, HDACi reduces ferroptosis suppressor protein (FSP1) by promoting its mRNA degradation. Specifically, it is confirmed that HDACi specifically targets HDAC1 and promotes the H3K27ac modification of fat mass- and obesity-associated gene (FTO) and AlkB Homolog 5, RNA Demethylase (ALKBH5), which results in significant activation of FTO and ALKBH5. The activation of FTO and ALKBH5 reduces N6-methyladenosine (mA) modification on FSP1 mRNA, leading to its degradation. Crucially, lactylation of HDAC1 is essential for ferroptosis regulation. Both Vorinostat (SAHA) and Trichostatin A (TSA) notably diminish HDAC1 lactylation in comparison to other HDAC1 inhibitors, exhibiting a consistent trend of increasing susceptibility to ferroptosis. In conclusion, the research reveals that HDACi decreases HDAC1 lactylation to sensitize CRC to ferroptosis and that the combination of HDACi and ferroptosis inducers can be a promising therapeutic strategy for CRC.
结直肠癌（CRC）对铁死亡具有高度抗性，这阻碍了抗铁死亡疗法的应用。通过药物筛选发现，组蛋白去乙酰化酶抑制剂（HDACi）可显著增强CRC对铁死亡的敏感性。HDACi与铁死亡诱导剂联合使用在体内和体外均能协同抑制CRC的生长。机制上，HDACi通过促进铁死亡抑制蛋白（FSP1）的mRNA降解来降低FSP1。具体而言，已证实HDACi特异性靶向HDAC1，并促进脂肪量和肥胖相关基因（FTO）和AlkB同源物5、RNA去甲基化酶（ALKBH5）的H3K27ac修饰，从而导致FTO和ALKBH5的显著激活。FTO和ALKBH5的激活减少了FSP1 mRNA上的N6-甲基腺苷（m6A）修饰，导致其降解。至关重要的是，HDAC1的乳酸化对于铁死亡调节至关重要。与其他HDAC1抑制剂相比，伏立诺他（SAHA）和曲古抑菌素A（TSA）均显著降低HDAC1乳酸化，呈现出对铁死亡敏感性增加的一致趋势。总之，该研究表明HDACi通过降低HDAC1乳酸化使CRC对铁死亡敏感，且HDACi与铁死亡诱导剂联合使用可能是一种有前景的CRC治疗策略。
