Yingying Shang, Qi Yao, Ya Tan, Ruipeng Bian, Yanni Ma, Yuanze Zhou, Rong Mu, Nahua Xu, Yanyun Shi, Nan Lu, Lin Liu, Jieping Chen, Shuangnian Xu, Hui Li
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引用次数: 0
Abstract
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.
期刊介绍:
Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.