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HERP constrains white adipose expansion and inflammation by STEAP4 stabilization

Cell Death & Differentiation (2025)Cite this article

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Abstract

Obesity is defined as excessive white adipose tissue (WAT) expansion and adipose inflammation. HERP is a crucial member of the ERAD machine and plays a critical role in protein degradation. Nevertheless, its role in adipose tissue remains uncharacterized. Here we identify HERP as a nutrient-sensing factor. When fed a low-fat diet, both male and female HERP-KO mice exhibited adipose expansion and mild metabolic disturbances without altered body weight. Conversely, high-fat diet-fed HERP-KO mice developed exacerbated obesity, adipose expansion, and severe metabolic disorders. Further analysis revealed that HERP deficiency stimulated adipogenesis/lipogenesis and inflammation in WAT and primary adipocytes, driving the observed phenotypes. Intriguingly, chronic HFD exposure induced adipogenic/lipogenic resistance in HERP-deficient WAT. Mechanistically, HERP interacted with STEAP4 to prevent its ubiquitin-mediated degradation. HERP regulates adipogenesis through STEAP4 in a PPARγ-dependent manner. Enhancing STEAP4 expression ameliorated adipose expansion, obesity, and metabolic disorders in HERP-KO mice by suppressing adipogenesis/lipogenesis and inflammation in WAT. Clinically, HERP and STEAP4 expression inversely correlate with BMI, showing reduced levels in overweight individuals. Collectively, our study establishes HERP as a protective factor against adipose expansion and inflammation, revealing potential therapeutic strategies for obesity.

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Fig. 1: HERP KO mice exhibit adipose expansion and mild metabolic disorders on a low-fat diet.
Fig. 2: HERP deficiency exacerbates high-fat diet induced obesity, adipose expansion, and metabolic disorders.
Fig. 3: HERP deficiency promotes adipogenesis/lipogenesis and inflammation in white adipose tissue.
Fig. 4: HERP deficiency induces adipogenesis/lipogenesis resistance but exacerbates inflammation in adipose tissue during long-term HFD feeding.
Fig. 5: HERP ablation provokes adipogenesis/lipogenesis and inflammation in primary adipocytes.
Fig. 6: HERP interacts with STEAP4 to protect it from ubiquitin-proteasome degradation in vivo and in vitro.
Fig. 7: Enhancement of STEAP4 expression ameliorates obesity, adipose expansion and metabolic disorders in HERP KO mice.
Fig. 8: The expression pattern of HERP and STEAP4 in human subcutaneous adipose tissue.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request. Original uncropped western blot images have been included in the Supplementary Information.

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Funding

This work was supported by National Natural Science Foundation of China (82000830 and 82341066); Excellent Young Researchers Program of the 5th Affiliated Hospital of SYSU (WYYXQN-2021007); the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine Foundation of Guangdong Province (2023LSYS001).

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Authors and Affiliations

  1. Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China

    Yingchun Chen, Yanyan Wu, Haorui Qin & Fei Xiao

  2. Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China

    Yingchun Chen & Fei Xiao

  3. Department of Plastic and Aesthetic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China

    Zhiqiang Han

  4. Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China

    Yao Tang & Fei Xiao

  5. Center for Genomic and Personalized Medicine, Guangxi Medical University, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, China

    Qiuyan Wang

  6. State Key Laboratory of Anti-Infective Drug Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China

    Fei Xiao

  7. Kashi Guangdong Institute of Science and Technology, The First People’s Hospital of Kashi, Kashi, Xinjiang Uygur Autonomous Region, China

    Fei Xiao

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Contributions

FX, YC and QW conceived the project and designed the experiments. YC performed the experiments, processed the data, and wrote the manuscript. YW, HQ and YT assisted the animal experiments. ZH collected human subcutaneous adipose tissues.

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Correspondence to Yingchun Chen, Qiuyan Wang or Fei Xiao.

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Chen, Y., Wu, Y., Qin, H. et al. HERP constrains white adipose expansion and inflammation by STEAP4 stabilization. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01608-2

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