Sex-specific regulation of <i>SLC39A11</i> in the murine liver

Xiaopeng Li; Yanhan Feng; Biyao Tang; Enjun Xie; Jiaming Wang; Junxia Min; Fudi Wang; Zhidan Xia

doi:10.1016/j.jgg.2026.04.003

Volume 53 Issue 9

Sep. 2026

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Article Navigation > Journal of Genetics and Genomics > 2026 > 53(9): 1718-1730

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Sex-specific regulation of SLC39A11 in the murine liver

doi: 10.1016/j.jgg.2026.04.003

a. The Second Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;
b. Food Science and Nutrition Center, Hunan Institute of Agricultural Product Processing and Quality Safety, Hunan Academy of Agricultural Sciences, Changsha, Hunan 410125, China

Funds:

This work was supported by grants from the National Natural Science Foundation of China (32200961 to Xiaopeng Li, 32371222 to Zhidan Xia, 82471593 to Junxia Min, and 32330047 to Fudi Wang), and the Science and Technology Innovation Program of Hunan Province (2024RC3239 to Xiaopeng Li). The authors thank Jingyao Chen at the Core Facility for Histomorphology of Zhejiang University School of Medicine for providing technical support.

Received Date: 2025-11-25
Accepted Date: 2026-04-05
Rev Recd Date: 2026-03-27

Available Online: 2026-09-07

Publish Date: 2026-09-30

Abstract

Abstract

Sex differences in health and disease are evident in humans and many other animal species. However, the sex-related determinants are less understood, and the underlying mechanisms remain elusive. By analyzing the RNA-seq data, we unexpectedly find that Slc39a11 is significantly associated with the non-alcoholic fatty liver disease pathway only in female mice, revealing a sex-specific role of Slc39a11 in liver metabolism. We then generate tissue-specific SLC39A11 knock-in and Slc39a11 knockout mice and find that female but not male SLC39A11-liver conditional overexpression (LKI) mice develop more severe cholestasis and liver injury compared to controls when fed a methionine/choline-deficient (MCD) diet. In contrast, female Slc39a11-liver conditional knockout (LKO) mice exhibit attenuated liver injury under MCD feeding. Ovariectomy in female mice largely reversed these phenotypes. Interestingly, female SLC39A11-intestine-specific overexpression (IKI) mice show alleviated liver damage, whereas female Slc39a11-intestine-specific knockout (IKO) mice develop exacerbated liver injury under MCD feeding; these effects are not observed in male SLC39A11-IKI or Slc39a11-IKO mice. This study reveals that SLC39A11 regulates liver metabolism both intrinsically and via the gut-liver axis through an evolutionarily conserved, sexual dimorphism mechanism, partially involving estrogen signaling and manganese metabolism, suggesting SLC39A11 is a potential target for the diagnosis and treatment of hepatobiliary diseases.
- SLC39A11,
- Gender difference,
- Liver injury,
- Cholestasis,
- Conditional knockout,
- Conditional knock-in,
- Manganese

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References(46)

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