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UFL1 alleviates ER stress and apoptosis stimulated by LPS via blocking the ferroptosis pathway in human granulosa-like cells


Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1) is a unique E3 ligase of the UFMylation system. Recent studies have shown that this enzyme plays a crucial role in the processes of endoplasmic reticulum stress (ER stress) and apoptosis. Lipopolysaccharide (LPS) can cause injury to ovarian granule cells and hinder follicular development by triggering ER stress and apoptosis. Our study aimed to investigate the mechanism by which UFL1 alleviates ER stress and apoptosis caused by LPS in human granulosa-like cells (KGNs). In this study, we found that the protein levels of UFL1 were increased obviously under LPS stimulation in KGNs and that ER stress and apoptosis were further aggravated when UFL1 was knocked down; in contrast, these events were rescued when UFL1 was overexpressed. Next, we showed that the levels of ferroptosis-related proteins were relatively altered, accompanied by the accumulation of reactive oxygen species (ROS) and Fe2+, following the inhibition of UFL1 expression. In contrast, the overexpression of UFL1 reversed the ferroptosis process by regulating the P53/SLC7A11 (solute carrier family 7, member 11, SLC7A11) system and autophagy in response to LPS stimulation. Furthermore, apoptosis and ER stress in KGNs are rescued by the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Collectively, our research demonstrated a new mechanism for UFL1 that can alleviate ER stress and apoptosis stimulated by LPS; this occurred via the regulation of the ferroptosis pathway in KGNs and may provide a new strategy for research in the field of reproduction.

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The authors thank all of the members in their lab. We are grateful to the Nanchang University Medical Department for providing technical support and abundant resources for our research group. Thanks to the National Natural Science Foundation for providing financial support for us. The authors would like to express their gratitude to EditSprings ( for the expert linguistic services provided.


This research was funded by the National Natural Science Foundation of China grant number (81860263) and the Natural Science Foundation of Jiangxi Province grant number (20192BAB205119).

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Conceptualization: Jingyi Li, Xiangting Tang; methodology: Jingyi Li, Xuer Tu; investigation: Jingyi Li, Zhe Jin; statistical analyses: Jingyi Li, Hao Dong; writing—original draft preparation: Jingyi Li, Qi Yang, Ting Yao; writing—review and editing: Jingyi Li, Xiangting Tang; funding acquisition: Zezheng Pan; resources: Zezheng Pan; project administration: Jingyi Li, Zezheng Pan. All authors read and approved the final manuscript.

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Correspondence to Zezheng Pan.

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The authors declare no competing interests.

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Li, J., Tang, X., Tu, X. et al. UFL1 alleviates ER stress and apoptosis stimulated by LPS via blocking the ferroptosis pathway in human granulosa-like cells. Cell Stress and Chaperones (2022).

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  • UFL1
  • ER stress
  • Apoptosis
  • Ferroptosis