Puerarin Targets MIC19 to Suppress Mitochondrial Metabolism of Tumor-Infiltrating Tregs and Enhance Anti-tumor Immunity

  • Adv Sci (Weinh). 2025 Nov 18:e12793. doi: 10.1002/advs.202512793.
Yu Li  1  2  3 ,  Ziyan Song  1 ,  Jianjun Ding  4 ,  Yiheng Zhou  1 ,  Tianning Huang  1 ,  Qufei Qian  1 ,  Miao Yu  1 ,  Wenzhao Chen  1 ,  Jiazheng Liu  5 ,  Ling Lu  1 ,  Qiuyang Chen  1
Affiliations
  • 1. Collaborative Innovation Center for Cancer Personalized Medicine and Hepatobiliary Center, The First Hospital Affiliated with Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
  • 2. Department of General Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, No. 71 Hexi Street, Nanjing, Jiangsu, 210019, China.
  • 3. Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, No. 146 Hanzhong Road, Nanjing, Jiangsu, 210029, China.
  • 4. School of Food Science and Technology, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu, 214122, China.
  • 5. State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, 999078, China.
PMID: 41250935 DOI: 10.1002/advs.202512793
Abstract

Regulatory T cells (Tregs) are pivotal mediators of immunosuppression in hepatocellular carcinoma, but strategies for selectively disrupting their function remain underdeveloped. Here, puerarin, a natural isoflavone is identifed as a selective immunometabolic modulator. It impairs Mitochondrial Metabolism in tumor-infiltrating Tregs (Ti-Tregs) without affecting conventional T cells. Mechanistically, puerarin directly binds to MIC19-a core subunit of the mitochondrial contact site and cristae organizing system-leading to its degradation and disruption of the MIC19-MIC60 complex. This disruption causes cristae disorganization, reduces Oxidative Phosphorylation, and weakens the immunosuppressive function of Ti-Tregs. In vivo, puerarin decreases Ti-Treg infiltration, thereby enhancing antitumor immunity without causing systemic toxicity. Furthermore, MIC19 knockdown and site-directed mutagenesis studies validate the role of critical MIC19 residues (His180, Gln187, and Tyr211) in puerarin's activity. These results reveal a mechanism by which puerarin suppresses Mitochondrial Metabolism of Ti-Tregs and emphasize the therapeutic potential of natural compounds in metabolic targeting for Cancer Immunotherapy.

Keywords
Regulator T cells; hepatocellular carcinoma; immunotherapy; mitochondrial metabolism; puerarin.
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