2. Academic Validation
  3. CXCR3 inhibition ameliorates mitochondrial function to mitigate oxidative damage through NCOA4-mediated ferritinophagy and improves the gut microbiota in mice

CXCR3 inhibition ameliorates mitochondrial function to mitigate oxidative damage through NCOA4-mediated ferritinophagy and improves the gut microbiota in mice

  • Free Radic Biol Med. 2025 Mar 1:229:384-398. doi: 10.1016/j.freeradbiomed.2025.01.034.
Yuan Gao 1,  Yian Deng 1,  Wenjie Li 1,  Junjie Wang 1,  Mingze Liu 1,  Hanchuan Dai 2
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, China.
  • 2 College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, China. Electronic address: daihch@mail.hzau.edu.cn.
PMID: 39827924 DOI: 10.1016/j.freeradbiomed.2025.01.034
Abstract

Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy contributes to maintain intracellular iron balance by regulating ferritin degradation, which is essential for redox homeostasis. CXC-motif Chemokine Receptor 3 (CXCR3) is involved in the regulation of oxidative stress and Autophagy. However, its role in modulating intestinal oxidative damage through ferritinophagy and the gut microbiota remains unclear. In this study, the impacts of CXCR3 inhibition on intestine oxidative damage, ferritinophagy, and the gut microbiota, as well as the mitochondrial quality control were investigated both in vivo and in vitro. The results show that CXCR3 inhibition by AMG487 relieves Diquat-induced intestinal damage, enhances the expression of tight junction proteins, and promotes antioxidant capacity in mice. Simultaneously, CXCR3 inhibition improves gut microbiota composition, and triggers NCOA4-mediated ferritinophagy. Mechanistically, the effects of CXCR3 inhibition on ferritinophagy were explored in IPEC-J2 cells. Co-localization and interaction between CXCR3 and NCOA4 were observed. Downregulation of NCOA4-mediated ferritinophagy leads to increase the expression of tight junction proteins, reduces iron levels, restricts ROS accumulation, and enhances GPX4 expression. Moreover, CXCR3 suppression facilitates mitochondrial biogenesis and mitochondrial fusion, increases antioxidative capacity, and results in the elevation of tight junction proteins expression. These findings suggest that CXCR3 inhibition reverses Diquat-induced intestinal oxidative damage, enhances mitochondrial function, and improves gut microbiota composition by elevating NCOA4-mediated ferritinophagy, which implies that CXCR3 may serve as a potential therapeutic intervention targeting iron metabolism for treating intestinal diseases.

Keywords

AMG487; CXCR3; Ferritinophagy; Gut microbiota; Oxidative damage.

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