Shang Yingying, Yao Qi, Tan Ya, Bian Ruipeng, Ma Yanni, Zhou Yuanze, Mu Rong, Xu Nahua, Shi Yanyun, Lu Nan, Liu Lin, Chen Jieping, Xu Shuangnian, Li Hui
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
Mol Carcinog. 2025 Jul 17. doi: 10.1002/mc.70016.
Ferroptosis, an iron-dependent form of programmed cell death, is emerging as a novel approach to tackling cancer. Cancer cells require large amounts of iron for their rapid growth, making them intrinsically vulnerable to ferroptosis. However, cancer cells have developed several important antioxidant pathways to counteract ferroptosis. One of these key pathways is the FSP1/CoQH2 pathway. In this study, we reveal a new regulatory mechanism of FSP1 involving the Pregnane X Receptor (PXR). Activation of PXR by rifaximin and rifampicin suppresses ferroptosis in a variety of cancer cells from different origins. The protective effect of rifaximin and rifampicin is lost in PXR knockout cells or in the presence of PXR inhibitor, validating the role of PXR in mediating the effects of these drugs. Additionally, rifaximin and rifampicin decrease lipid peroxidation and ferrous iron accumulation during ferroptosis induction, effects that are reversed in PXR knockout cells. Mechanistically, rifaximin and rifampicin induce the expression of FSP1 in a PXR-dependent manner, as they fail to induce FSP1 in PXR knockout cells. Furthermore, the ferroptosis protection effect of rifaximin and rifampicin is significantly compromised in FSP1 knockout cells or in the presence of the FSP1 inhibitor iFSP1. Importantly, we demonstrated that the PXR inhibitor pimecrolimus showed synergy with ferroptosis inducer sulfasalazine to repress tumor growth in vivo. Together, these findings provide evidence supporting an anti-ferroptosis role of PXR through the upregulation of FSP1 expression.
铁死亡是一种铁依赖性的程序性细胞死亡形式，正成为一种治疗癌症的新方法。癌细胞的快速生长需要大量铁，这使它们本质上易受铁死亡影响。然而，癌细胞已经发展出几种重要的抗氧化途径来对抗铁死亡。其中一个关键途径是FSP1/辅酶QH2途径。在本研究中，我们揭示了一种涉及孕烷X受体（PXR）的FSP1新调控机制。利福昔明和利福平激活PXR可抑制来自不同来源的多种癌细胞中的铁死亡。在PXR基因敲除细胞中或存在PXR抑制剂时，利福昔明和利福平的保护作用消失，这证实了PXR在介导这些药物作用中的作用。此外，利福昔明和利福平在铁死亡诱导过程中减少脂质过氧化和亚铁积累，而在PXR基因敲除细胞中这些作用会逆转。从机制上讲，利福昔明和利福平以PXR依赖的方式诱导FSP1的表达，因为它们在PXR基因敲除细胞中无法诱导FSP1。此外，在FSP1基因敲除细胞中或存在FSP1抑制剂iFSP1时，利福昔明和利福平的铁死亡保护作用显著受损。重要的是，我们证明PXR抑制剂吡美莫司与铁死亡诱导剂柳氮磺胺吡啶在体内显示出协同作用以抑制肿瘤生长。总之，这些发现提供了证据支持PXR通过上调FSP1表达发挥抗铁死亡作用。
