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

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<sup>+</sup> 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<sup>+</sup> 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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Publication Details

Journal
Nature Communications
Published
2025-10-29
DOI
https://doi.org/10.1038/s41467-025-64572-y
Citations
2
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
3.04

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article

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

Jiashuo Chao, Feng Cheng, Mu Liu, Ziyu Xun et al.
2 citations
Nature Communications
Ferroptosis and cancer prognosis
3.04
article

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

Jiashuo Chao, Feng Cheng, Mu Liu, Ziyu Xun, Ling Lü, Yuan Liang, Haitao Zhao, Mingming Wang, Yuhan Zhang, Shanshan Wang, Hao Wang, Lei Zhang, Qiyuan Huang, Bingbing Shou, Zhengfeng Xuan, Rui Zhang
article en
2 citations

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<sup>+</sup> 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<sup>+</sup> 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.

Nature CommunicationsVol. 16(1)
University of California, Los Angeles (US), Xuzhou Medical College (CN), Xiamen University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), China-Japan Friendship Hospital (CN), Peking Union Medical College Hospital (CN), First Affiliated Hospital of Xiamen University (CN), Zhejiang Cancer Hospital (CN), Zhongshan Hospital of Xiamen University (CN), Jiangsu Province Hospital (CN), Hangzhou Cancer Hospital (CN), Southeast University (CN), Nanjing Medical University (CN)
Peking Union Medical College Hospital, Fundamental Research Funds for the Central Universities
Openalex Percentile: Top 7%
Ferroptosis and cancer prognosis
3.04
DOIOpen Access PDFOpenAlex
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