A dysregulated hepcidin-iron axis impairs antiviral immunity and induces lethal liver pathology in neonates
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<sup>+</sup> 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.
Authors
- Wan‐Yang Sun (ORCID: https://orcid.org/0000-0002-4439-967X)
- Zhanghua Chen (ORCID: https://orcid.org/0000-0002-2505-0675)
- Kanghua Zhong (ORCID: https://orcid.org/0000-0003-1386-7087)
- Xiaoqiong Gu (ORCID: https://orcid.org/0000-0002-9558-4226)
- Rongli Fang
- Wen Lei (ORCID: https://orcid.org/0000-0001-5473-5350)
- Jiankun Liang (ORCID: https://orcid.org/0000-0003-2204-4701)
- Qiuming He
- Rong‐Rong He (ORCID: https://orcid.org/0000-0001-5505-5672)
- Weiwei Liang
- Huimin Xia (ORCID: https://orcid.org/0000-0002-0103-1672)
- Zhi Q. Yao (ORCID: https://orcid.org/0000-0002-1848-1071)
- Xixi Chen (ORCID: https://orcid.org/0000-0001-9646-8828)
- Wenhao Zhou (ORCID: https://orcid.org/0000-0002-3290-4720)
- Yanhui Xu (ORCID: https://orcid.org/0000-0003-3526-3612)
- Chengwei Chai (ORCID: https://orcid.org/0000-0001-6680-7307)
- Andrew M. Lew (ORCID: https://orcid.org/0000-0002-2198-8164)
- Tingting Chen (ORCID: https://orcid.org/0009-0006-9485-6740)
- Ming Liu (ORCID: https://orcid.org/0000-0002-5244-2973)
- Xiaolei Wang (ORCID: https://orcid.org/0000-0002-6964-2453)
- Zhe Wen (ORCID: https://orcid.org/0000-0002-6062-1242)
- Yanfang Zhang (ORCID: https://orcid.org/0000-0001-9309-7347)
- Ning Yu (ORCID: https://orcid.org/0000-0002-3046-4338)
- Xiaotian Li (ORCID: https://orcid.org/0000-0002-2051-4581)
- Huifang Ren
- Zefeng Lin (ORCID: https://orcid.org/0000-0001-7532-9175)
- Yuxia Zhang (ORCID: https://orcid.org/0000-0003-2715-0925)
- Yuanyuan Luo (ORCID: https://orcid.org/0009-0007-0889-5098)
- Jinbao Liu (ORCID: https://orcid.org/0000-0003-2220-2407)
- Yunnan Xiao
- Zhenhua Luo (ORCID: https://orcid.org/0000-0002-6516-8555)
- Qifeng Liang
- Haibiao Gong
- Junqiang Lv (ORCID: https://orcid.org/0000-0002-0434-8683)
Institutions
- Sun Yat-sen University (CN)
- Jinan University (CN)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Sichuan International Studies University (CN)
- Liuzhou Maternal and Child Health Hospital (CN)
- Guangzhou Women and Children Medical Center (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Guangdong Province Women and Children Hospital (CN)
- Tianjin Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Immunity
- Published
- 2025-12-08
- DOI
- https://doi.org/10.1016/j.immuni.2025.11.001
- Primary Topic
- Pediatric Hepatobiliary Diseases and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00