2. Academic Validation
  3. FAD synthase confers ferroptosis resistance and restrains CD8+ T cell recruitment in hepatocellular carcinoma

FAD synthase confers ferroptosis resistance and restrains CD8+ T cell recruitment in hepatocellular carcinoma

  • Nat Commun. 2025 Oct 29;16(1):9547. doi: 10.1038/s41467-025-64572-y.
Jiashuo Chao # 1 2 3 4,  Yuan Liang # 5,  Hao Wang # 3,  Ziyu Xun # 1,  Shanshan Wang # 6,  Zhengfeng Xuan # 1,  Mingming Wang 1,  Qiyuan Huang 3,  Rui Zhang 2,  Mu Liu 3,  Lei Zhang 3,  Bohang Shou 7,  Yuhan Zhang 8,  Feng Cheng 9,  Haitao Zhao 10,  Ling Lu 11 12
Affiliations

Affiliations

  • 1 Department of Liver Surgery, Peking Union Medical College Hospital, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China.
  • 2 Jiangsu Key Laboratory of Organ Transplantation and Transplant Immunology and Hepatobiliary Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 5 School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
  • 6 Department of Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 7 Department of Life Science, University of California Los Angeles, Los Angeles, CA, USA.
  • 8 China-Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China.
  • 9 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. docchengfeng@njmu.edu.cn.
  • 10 Department of Liver Surgery, Peking Union Medical College Hospital, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China. zhaoht@pumch.cn.
  • 11 Jiangsu Key Laboratory of Organ Transplantation and Transplant Immunology and Hepatobiliary Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. lvling@njmu.edu.cn.
  • 12 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. lvling@njmu.edu.cn.
  • # Contributed equally.
PMID: 41162372 DOI: 10.1038/s41467-025-64572-y
Abstract

Vitamin B2 (VB2) metabolism regulates numerous cellular processes, but its role in hepatocellular carcinoma (HCC) progression remains unclear. Here we show that HCC tumors are characterized by upregulation of a VB2 metabolism signature, and VB2 metabolism promotes HCC progression. Among VB2 metabolic Enzymes, flavin adenine dinucleotide synthase (FADS) is the only one that is widely overexpressed in human HCC. Elevated FADS expression correlates with resistance to anti-PD-1 therapy and poor prognosis. In vivo, FADS facilitates HCC cell growth and suppresses T cell-mediated antitumor immunity. Single-cell transcriptomic analysis reveals that FADS-induced changes occur both in the tumor cells and the intra-tumoral CD8+ T cells. Knocking down FADS induces HCC cell death and increases CD8⁺ T cell infiltration. Mechanistically, FADS confers Ferroptosis resistance on HCC cells via enzymatic function to produce FAD and non-enzymatic function to stabilize PCBP2. Moreover, FADS impairs CD8+ T cell recruitment by disrupting the cGAS-STING pathway. Hesperidin, a clinically approved FADS inhibitor, shows antitumor efficacy in a mouse model. Our study thus highlights the importance of VB2 metabolism in HCC and provides the proof of principle for targeting FADS as a therapeutic strategy for HCC.

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