GPX4 is not required for the thermogenesis function of brown adipose tissue in mice

Abstract

Aims: Brown adipose tissue (BAT) relies heavily on mitochondrial activity and reactive oxygen species homeostasis to regulate thermogenesis and metabolic balance. However, the specific role of glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme and central regulator of ferroptosis, in BAT remains unclear. This study aims to investigate the necessity of GPX4 for the functional integrity and thermogenic capacity of BAT.
Methods: Initially, we employed pharmacological inhibition of GPX4 in vitro using differentiated brown adipocytes. To investigate its role in vivo, we generated a BAT-specific Gpx4 knockout mouse model. The physiological and metabolic impacts of GPX4 deficiency were evaluated across three different conditions: cold exposure, high-fat diet, and vitamin E-deficient diet. Comprehensive evaluations were conducted using metabolic, histological, ultrastructural, and transcriptomic (RNA-seq) analyses.
Results: In vitro, pharmacological inhibition of GPX4 induced ferroptosis in differentiated brown adipocytes, suggesting its potential regulatory role. Strikingly, in vivo histological, ultrastructural, and metabolic analyses indicated that the genetic deletion of GPX4 does not impair BAT morphology or thermogenic function under any of the tested conditions. Consistent with these physiological findings, RNA-seq revealed that GPX4 deficiency did not significantly alter the expression of genes associated with ferroptosis or thermogenic pathways.
Conclusion: Although pharmacological inhibition of GPX4 triggers ferroptosis in brown adipocytes in vitro, GPX4 is not essential for maintaining the morphological integrity and thermogenic capacity of BAT in vivo under the specific experimental conditions tested.

Keywords

Glutathione peroxidase 4 / thermogenesis / brown adipose tissue

Acknowledgements

We are grateful to Prof. Zhinan Yin (Jinan University, Guangzhou, China) for generously providing the Ucp1-CreERT2 mouse strains essential for this study. The authors acknowledge the use of DeepSeek-V4 for language editing and polishing of the manuscript. No AI tool was used for data analysis, figure generation, or scientific interpretation. The authors take full responsibility for the integrity, originality, and accuracy of the work.

Authors contribution

Hu Q: Conceptualization, writing-original draft, supervision, data curation, writing-review & editing. Ju Z, Wang F: Conceptualization, supervision, data curation, writing-review & editing. Zhang Y: Methodology, investigation, writing-original draft, data curation, writing-review & editing. Wang W, Li C, You W: Methodology, investigation, data curation, writing-review & editing. Liu Y: Formal analysis, data curation, visualization, writing-review & editing.

Conflicts of interest

Fudi Wang is an Editorial Board Member of Ferroptosis and Oxidative Stress. The other authors declare no conflicts of interest.

Ethical approval

All animal procedures were carried out in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of Experimental Animal Center of Jinan University. The study protocol was reviewed and approved by the Animal Care and Ethics Committee of Jinan University (Approval No. 20240731-12).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The data and materials supporting the findings of this study are available from the supplementary materials and corresponding authors upon reasonable request.

Funding

This work was supported by the Guangzhou Science and Technology Program (Grant No. 2024A04J4046), the Innovation Team Project of Universities in Guangdong Province (Grant No. 2023KCXTD004), and the National Key R&D Program of China (Grant No. 2021YFA1100103).

Copyright

© The Author(s) 2026.

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