Abstract
Exposure to zearalenone (ZEN), an estrogen-like mycotoxin produced by Fusarium fungi, impairs reproductive performance and farm-animal welfare; however, the underlying mechanism remains unclear. Using female pigs as the large animal model, we demonstrate that ZEN-induced reproductive lipotoxicity is associated with alterations in estrogen receptor-alpha (ERα) expression, diacylglycerol levels, and pro-inflammatory cytokine production. Mechanistically, upregulated ERα directly binds to the promoter regions of Cd36 and Tlr4 in the nucleus, leading to increased expression of the lipid transporter CD36 and the inflammatory receptor TLR4, as well as enhanced CD36-TLR4 interaction. This subsequently results in diacylglycerol accumulation and inflammation. Consistently, studies using Cd36-knockout mice and the TLR4-specific inhibitor TAK-242 reveal that ZEN-induced reproductive lipotoxicity is dependent on the ERα-CD36/TLR4 axis. Furthermore, dietary supplementation with the ZEN-degrading enzyme ZLHY-6 in female pigs also counteracts ZEN-induced reproductive lipotoxicity through the inhibition of the ERα-CD36/TLR4 signaling pathway. Together, these findings reveal a novel mechanism underlying ZEN-induced reproductive lipotoxicity, and highlight the ERα-CD36/TLR4 axis as a potential therapeutic target.
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Data availability
The RNA-seq dataset generated and analyzed in this study is publicly available for download in the National Center for Biotechnology Information Gene Expression Omnibus (BioProject ID: PRJNA1136154). The data that support the findings of this study are available from the corresponding author upon reasonable request. The internal standards for lipidomics are provided in Supplementary Data 1. The data source for all Graphs in this study is provided in Supplementary Data 2. Uncropped and unedited blot are provided in Supplementary Information as Supplementary Fig. 9.
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Acknowledgements
The work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XD C0110304 to X.W), the National Key Research and Development Program of China (2023YFF1104600 to C.P.S), the National Natural Science Foundation of China (No. 32571297 to S.J.W and No. 82300970 to Y.L), the Sichuan Science and Technology Program (No. 2025ZNSFSC0170 to W.F).
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Chao Dai: Writing– original draft, Visualization, Validation, Methodology. Wei Fu: Writing– review & editing, Software, Methodology, Formal analysis, Data curation. YuanMeng Huang: Writing– review & editing, Formal analysis, Resources, Methodology. Tiantian Li: Formal analysis, Resources, Methodology. Zifeng Ma: Formal analysis, Methodology. Xiaojiao Chang: Data curation, Methodology. Changpo Sun: Resources, Project administration. Shujin Wang: Writing– original draft & review & editing, Resources, Funding acquisition, Software, Supervision, Conceptualization. Xin Wu: Writing– review & editing, Resources, Funding acquisition. Yang Li: Writing–review & editing, Resources, Project administration, Funding acquisition.
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All Institutional and National Guidelines for the care and use of animals (fisheries) were followed. The animal experiments in this study received approval from the Animal Care and Use Committee at Chongqing Medical University (approval number: 2019201) and the Animal Welfare Committee of the Institute of Subtropical Agriculture, Chinese Academy of Sciences (approval number: 20160615-013).
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Dai, C., Fu, W., Huang, Y. et al. Zearalenone causes female reproductive lipotoxicity through the ERα-CD36/TLR4 signaling pathway. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09953-9
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DOI: https://doi.org/10.1038/s42003-026-09953-9
