2. Academic Validation
  3. HERP constrains white adipose expansion and inflammation by STEAP4 stabilization

HERP constrains white adipose expansion and inflammation by STEAP4 stabilization

  • Cell Death Differ. 2025 Nov 17. doi: 10.1038/s41418-025-01608-2.
Yingchun Chen 1 2,  Yanyan Wu 3,  Haorui Qin 3,  Zhiqiang Han 4,  Yao Tang 5,  Qiuyan Wang 6,  Fei Xiao 7 8 9 10 11
Affiliations

Affiliations

  • 1 Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China. [email protected].
  • 2 Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China. [email protected].
  • 3 Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
  • 4 Department of Plastic and Aesthetic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
  • 5 Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
  • 6 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. [email protected].
  • 7 Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China. [email protected].
  • 8 Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China. [email protected].
  • 9 Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China. [email protected].
  • 10 State Key Laboratory of Anti-Infective Drug Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 11 Kashi Guangdong Institute of Science and Technology, The First People's Hospital of Kashi, Kashi, Xinjiang Uygur Autonomous Region, China. [email protected].
PMID: 41249464 DOI: 10.1038/s41418-025-01608-2
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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