2. Academic Validation
  3. The S100A8/A9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice

The S100A8/A9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice

  • Cell Metab. 2026 May 5;38(5):909-928.e8. doi: 10.1016/j.cmet.2026.02.005.
Lin Gao 1,  Ying Liu 2,  Ying Yu 2,  Yingga Wu 3,  Huanan Zhang 4,  Cui Wang 5,  Xinrui Gao 6,  Yang Chen 7,  Tingjie Zhang 8,  Sixian Huang 7,  Zhonghui Zhang 9,  Zengguang Jin 2,  Jie Chen 2,  Haiyang Jing 2,  Dehuang Kong 2,  Yanlin Tian 10,  Jacques Togo 10,  Yong Lei 8,  Yi Huang 10,  Fan Xia 11,  Min Li 11,  Anyongqi Wang 10,  Chao Jia 12,  Sumei Hu 2,  Di Chen 2,  Xina Xie 13,  Lu Wang 4,  Jie Liu 6,  Xiaomeng Wu 9,  Changyong Tang 14,  Chaoqun Niu 2,  Zesong Li 15,  John R Speakman 16
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10049, China; Department of Medical Research Center, Yuebei People's Hospital Affiliated to Shantou University Medical College, Shaoguan 512026, China; Faculty of Pharmacy, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China.
  • 2 Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 3 Institute of Biomedical Sciences, Inner Mongolia University, Hohhot, China.
  • 4 School of Pharmacy, Yantai University, Yantai 264005, Shandong, China.
  • 5 Institute of Basic Medicine, School of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong 637199, Sichuan, China.
  • 6 School of Food and Health, Beijing Technology and Business University, Beijing 100048, China.
  • 7 Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China.
  • 8 Department of Nuclear Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
  • 9 School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China.
  • 10 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • 11 Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • 12 Chengdu Novel Medical Equipment Co., Ltd, Guangzhou, China.
  • 13 Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China.
  • 14 Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, Guangdong, China.
  • 15 Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China; Department of Medical Research Center, Yuebei People's Hospital Affiliated to Shantou University Medical College, Shaoguan 512026, China; Institute of Basic Medicine, School of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong 637199, Sichuan, China. Electronic address: [email protected].
  • 16 Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China; Faculty of Pharmacy, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China; School of Biological Sciences, University of Aberdeen, Aberdeen, UK. Electronic address: [email protected].
PMID: 41780522 DOI: 10.1016/j.cmet.2026.02.005
Abstract

Cancer cachexia is a wasting syndrome characterized by reduced food intake and lean and fat tissue loss. In mice, Cancer cachexia involved marked reductions in host fat and lean mass (particularly skeletal muscle), which were balanced by tumor growth. Using 15N tracing, the tumor gets protein (nitrogen) from both food intake and host tissue breakdown. Total energy expenditure remained unchanged due to metabolic compensation among the tumor, brown adipose tissue (BAT), and Other organs, a phenomenon also observed in people with Cancer. The decrease in Leptin caused by fat loss did not stimulate food intake or reduce energy expenditure. We show that S100 calcium-binding protein A8 and A9 (S100A8/A9) and complement 3 (C3) in the hypothalamus play a key role in the reduction of food intake and fat mass during Cancer cachexia. The peripheral administration of S100A8/A9 inhibitors and the hypothalamic knockdown of C3 significantly increased food intake and partially rescued fat and lean tissue loss.

Keywords

C3; S100A8/A9; cancer cachexia; energy balance; fat loss; food intake; mice; muscle loss.

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