2. Academic Validation
  3. Pregnane X Receptor Activation Induces Ferroptosis Resistance Through Upregulation of FSP1

Pregnane X Receptor Activation Induces Ferroptosis Resistance Through Upregulation of FSP1

  • Mol Carcinog. 2025 Jul 17. doi: 10.1002/mc.70016.
Yingying Shang 1,  Qi Yao 2 3,  Ya Tan 4,  Ruipeng Bian 2 3,  Yanni Ma 1,  Yuanze Zhou 1,  Rong Mu 5,  Nahua Xu 2 3,  Yanyun Shi 6,  Nan Lu 7,  Lin Liu 4,  Jieping Chen 1,  Shuangnian Xu 1,  Hui Li 2 3
Affiliations

Affiliations

  • 1 Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
  • 2 Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 3 NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing, China.
  • 4 Department of Hematology of the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Zunyi Medical University, Zunyi, China.
  • 6 Division of Liver Surgery and NHC Key Lab of Transplant Engineering and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
  • 7 Department of Basic Medical School, Chongqing Medical University, Chongqing, China.
PMID: 40674609 DOI: 10.1002/mc.70016
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.

Keywords

FSP1/CoQH2; PXR; ferroptosis; pimecrolimus; rifampicin; rifaximin.

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