高氯酸血根碱通过激活血红素加氧酶1（HMOX1）并抑制溶质载体家族7成员11（SLC7A11）/谷胱甘肽过氧化物酶4（GPX4）轴使结直肠癌对铁死亡敏感。

Dracorhodin perochlorate sensitizes colorectal cancer to ferroptosis by activating HMOX1 and inhibiting the SLC7A11/GPX4 axis.

作者信息

Niu Xuben, Wang Mingkun, Wang Maihuan, Liu Xiaoya, Zhang Yun, Zheng Peng, Zhang Shuomin, Liu Ting, Cao Zhen, Zhang Chaojun

机构信息

Department of General Surgery, School of Medicine, South China University of Technology, Guangzhou 510006, China; Department of General Surgery, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China.

Department of General Surgery, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China; Navy Clinical College, the Fifth School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, 230032, China.

出版信息

Int Immunopharmacol. 2025 Jun 17;158:114827. doi: 10.1016/j.intimp.2025.114827. Epub 2025 May 12.

DOI:10.1016/j.intimp.2025.114827

PMID:40359890

Abstract

BACKGROUND

Ferroptosis, an iron-dependent form of cell death mediated by lipid peroxidation, plays a critical role in tumor progression. The natural small molecule compound dracorhodin perchlorate (DP) exhibits antitumor activity, but its effects on colorectal cancer (CRC) and the underlying mechanisms remain unclear.

OBJECTIVE

This study aimed to elucidate the role and mechanism of DP in CRC development and ferroptosis promotion.

METHODS

Using RNA-Seq, molecular docking and molecular dynamics simulation, we observed ferroptosis levels and expression of HMOX1, SLC7A11, and GPX4 in CRC cells treated with DP. We also examined the impact of modulating HMOX1, SLC7A11, and GPX4 on DP-induced ferroptosis and antitumor effects.

RESULTS

DP inhibited various malignant behaviors of CRC cells and induced ferroptosis. Mechanistically, RNA-Seq, molecular dynamics simulations, and molecular docking studies have collectively confirmed that DP directly binds to the HO-1 molecule, thereby upregulating HO-1 expression and inducing iron overload. Additionally, DP downregulates the expression of SLC7A11 and GPX4, collectively promoting the occurrence of ferroptosis in CRC cells. The HO-1 inhibitor ZnPP and SLC7A11 overexpression significantly inhibited the antitumor activity and ferroptosis induced by DP. Hemin and ferroptosis inducers enhanced its therapeutic effectiveness. DP safely suppressed subcutaneous tumor growth and exhibited synergistic effects with cisplatin both in vitro and in vivo. HMOX1 knockdown weakened the ferroptosis induced by DP in CRC.

CONCLUSIONS

The findings strongly support the activation of HMOX1 by DP, downregulation of the SLC7A11/GSH/GPX4 axis, and induction of ferroptosis in CRC cells. DP inhibited CRC progression and acted synergistically when combined with cisplatin. Our research provides a scientific basis for the use of DP in the treatment of CRC and offers new insights into the application of traditional Chinese medicine in the fight against CRC.

摘要

背景

铁死亡是一种由脂质过氧化介导的铁依赖性细胞死亡形式，在肿瘤进展中起关键作用。天然小分子化合物高氯酸血竭素（DP）具有抗肿瘤活性，但其对结直肠癌（CRC）的影响及潜在机制尚不清楚。

目的

本研究旨在阐明DP在CRC发生发展及促进铁死亡中的作用和机制。

方法

利用RNA测序、分子对接和分子动力学模拟，我们观察了用DP处理的CRC细胞中的铁死亡水平以及HMOX1、SLC7A11和GPX4的表达。我们还研究了调节HMOX1、SLC7A11和GPX4对DP诱导的铁死亡和抗肿瘤作用的影响。

结果

DP抑制CRC细胞的多种恶性行为并诱导铁死亡。机制上，RNA测序、分子动力学模拟和分子对接研究共同证实DP直接与HO-1分子结合，从而上调HO-1表达并诱导铁过载。此外，DP下调SLC7A11和GPX4的表达，共同促进CRC细胞中铁死亡的发生。HO-1抑制剂ZnPP和SLC7A11过表达显著抑制DP诱导的抗肿瘤活性和铁死亡。血红素和铁死亡诱导剂增强了其治疗效果。DP安全地抑制皮下肿瘤生长，并在体外和体内与顺铂均表现出协同作用。HMOX1基因敲低减弱了DP在CRC中诱导的铁死亡。