A dysregulated hepcidin-iron axis impairs antiviral immunity and induces lethal liver pathology in neonates

Xu, Y; Chen, X; Fang, R; Wang, X; Zhang, Y; Ren, H; Xiao, Y; Ning, Y; Li, X; Chai, C; Lei, W; Zhong, K; Liang, J; Liang, Q; Luo, Y; He, Q; Lin, Z; Luo, Z; Liu, M; Liang, W; Chen, T; Gu, X; Liu, J; Lv, J; Yao, Z; Gong, HB; Sun, WY; He, RR; Lew, AM; Xia, H; Wu, Y; Zhou, W; Wen, Z; Chen, Z; Zhang, Y

Author(s): Xu, Y; Chen, X; Fang, R; Wang, X; Zhang, Y; Ren, H; Xiao, Y; Ning, Y; Li, X; Chai, C; Lei, W; Zhong, K; Liang, J; Liang, Q; Luo, Y; He, Q; Lin, Z; Luo, Z; Liu, M; Liang, W; Chen, T; Gu, X; Liu, J; Lv, J; Yao, Z; Gong, HB; Sun, WY; He, RR; Lew, AM; Xia, H; Wu, Y; Zhou, W; Wen, Z; Chen, Z; Zhang, Y;
Details: Publication Year 2026-01-13,Volume 59,Issue #1,Page 79-97 e11
Journal Title: Immunity
Abstract: Systemic rotavirus (RV) infection poses a substantial health challenge in neonates, but the underlying pathogenesis remains elusive. In RV-infected neonatal mice and infants with biliary atresia (BA), we discovered that persistent type I interferon (IFN-I) signaling upregulated hepcidin expression in hepatocytes and TREM2(+) macrophages. This impaired SLC40A1-mediated iron excretion, leading to lipid peroxidation- and ferroptosis-mediated tissue damage. In mice deficient in Slc40a1 in myeloid cells, iron accumulation promoted RV replication and IFN-I activation in Kupffer cells. Blocking IFN-I-hepcidin signaling and iron chelation reduced RV-induced tissue damage in mice. Folic acid suppressed IFN-I-hepcidin-iron signaling in mice, and in an open-label clinical trial, folic acid supplementation in infants with BA reduced cholangitis and liver transplantation rates. Our data show that hepcidin-iron dysregulation plays a critical role in neonatal RV infection and reveal therapeutic targets for BA and other RV-related neonatal diseases. The clinical trial was registered in the Chinese Clinical Trial Registry ChiCTR2100050992.
Publisher: Cell Press
Keywords: *Hepcidins/metabolism; Animals; Mice; *Iron/metabolism; Humans; *Liver/pathology/immunology/virology; *Rotavirus Infections/immunology/pathology; *Rotavirus/immunology/physiology; Animals, Newborn; Infant, Newborn; Biliary Atresia/immunology; Interferon Type I/metabolism; Ferroportin; Signal Transduction; Mice, Knockout; Hepatocytes/metabolism/immunology; Male; Female; Cation Transport Proteins/metabolism/genetics; Mice, Inbred C57BL; Folic Acid/therapeutic use; Infant; Kupffer cells; Slc40a1; TREM2(+) macrophage; biliary atresia; ferroptosis; folic acid; hepcidin and iron regulation; lipid peroxidation; neonatal rotavirus infection; type I interferon signaling
Research Division(s): Immunology
PubMed ID: 41365298
Publisher's Version: https://doi.org/10.1016/j.immuni.2025.11.001
Open Access at Publisher's Site: https://doi.org/10.1016/j.immuni.2025.11.001
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-22 10:03:40

Last Modified: 2026-01-22 10:03:53