Fructose 1-phosphate inhibits mannose phosphate isomerase to suppress hepatocellular carcinogenesis PMID: 42178306

ADC Targets in Oncology

2026-04-10

Fructose 1-phosphate inhibits mannose phosphate isomerase to suppress hepatocellular carcinogenesis

Signal Transduct Target Ther. 2026 May 25;11(1):195. doi: 10.1038/s41392-026-02695-4.

Yongqiang Wang ^# ¹ ² , Xiangyang Zhang ^# ³ ⁴ , Ningning Wang ^# ¹ ⁵ , Huimin Jiang ¹ , Ningning Liang ¹ ³ , Chenxi Du ¹ ⁶ , Chunzhao Yin ¹ ³ ⁶ , Rui Li ¹ ³ ⁶ , Lili Zhang ¹ , Qiaochu Tu ¹ ⁶ , Jingwen Lv ¹ , Haoran Ma ¹ , Xiaodong Xu ¹ , Xinran Kong ⁷ , Xin Chen ¹ , Guijun Liu ¹ , Shiting Chen ¹ , Hualing Xu ³ , Jun Qin ⁷ , Shengxian Li ⁸ , Yongzhen Tao ¹ , Shan Zeng ⁴ , Hong Shen ⁴ , Marcus D Goncalves ⁹ , Shanshan Zhong ¹⁰ , Huiyong Yin ¹¹ ¹² ¹³ ¹⁴

Affiliations

1. CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), University of Chinese Academy of Sciences, Beijing, China.
2. Tianfu Jincheng Laboratory, Chengdu, China.
3. Department of Biomedical Sciences, College of Biomedicine, Institute of Digital Medicine, Tung Biomedical Science Center, The Shenzhen Research Institute and Futian Research Institute, City University of Hong Kong, Hong Kong, China.
4. Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
5. WeiFang People's Hospital, Shandong Second Medical University, Shandong, China.
6. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
7. Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
8. Organ Transplant Center, Shanghai Chang Zheng Hospital, 2nd Hospital Affiliated with Naval Medical University, Shanghai, China.
9. NYU Grossman School of Medicine, New York, NY, USA.
10. Department of Biomedical Sciences, College of Biomedicine, Institute of Digital Medicine, Tung Biomedical Science Center, The Shenzhen Research Institute and Futian Research Institute, City University of Hong Kong, Hong Kong, China. [email protected].
11. CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), University of Chinese Academy of Sciences, Beijing, China. [email protected].
12. Tianfu Jincheng Laboratory, Chengdu, China. [email protected].
13. Department of Biomedical Sciences, College of Biomedicine, Institute of Digital Medicine, Tung Biomedical Science Center, The Shenzhen Research Institute and Futian Research Institute, City University of Hong Kong, Hong Kong, China. [email protected].
14. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
# Contributed equally.

Abstract

Fructose consumption increases the risk of obesity-related metabolic diseases and some cancers, but its role in hepatocellular carcinogenesis (HCC) remains controversial. Animal studies suggest that high fructose promotes HCC, whereas human data fail to support the positive link between fructose intake and elevated risk of liver Cancer. Moreover, fructose metabolism is progressively attenuated in HCC with the loss of key fructolytic Enzymes, including fructose-1,6-bisphosphate aldolase B (ALDOB). Here, we report that fructose suppresses HCC through fructose 1-phosphate (F1P)-mediated inhibition of mannose phosphate isomerase (MPI) in the context of ALDOB deficiency. Transcriptomic and metabolic flux analyses using human HCC cells and tissues revealed that liver Cancer cells retain a significant ability to metabolize fructose despite the downregulation of fructolytic genes, with ALDOB showing the earliest and most pronounced suppression compared with GLUT2 and KHK. Dietary supplementation with 10% fructose suppressed HCC in liver-specific Aldob knockout mice. Further spatial and single-cell transcriptomic analyses of clinical HCC samples revealed the spatiotemporal dynamics of fructolytic gene expression and identified subsets of Cancer cells that retain fructose uptake and phosphorylation capacity (SLC2A2⁺/KHK⁺) but lack ALDOB expression. Upon fructose exposure, accumulated F1P binds to and inhibits MPI, reducing protein N-glycosylation and triggering Apoptosis due to maladaptive ER stress. We further performed virtual high-throughput screening of FDA-approved and clinical-trial drugs and identified ebselen as a potent MPI inhibitor. Taken together, the results of our study reveal a novel mechanism by which dietary fructose inhibits HCC through the F1P-MPI axis, suggesting a therapeutic strategy targeting metabolic vulnerabilities in Cancer.