A sulfated pectin polysaccharide from Chrysanthemum morifolium induces ferroptosis in pancreatic cancer by stabilizing TFRC
- Carbohydr Polym. 2026 Jun 1:381:125224. doi: 10.1016/j.carbpol.2026.125224.
- 1. School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- 2. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan Tsuihang New District, Zhongshan, Guangdong, 528400, China.
- 3. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan Tsuihang New District, Zhongshan, Guangdong, 528400, China; Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, 519000, China.
- 4. Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Sciences, Fudan University, Shanghai, 201203, China.
- 5. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan Tsuihang New District, Zhongshan, Guangdong, 528400, China; Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: [email protected].
- 6. Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: [email protected].
- 7. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan Tsuihang New District, Zhongshan, Guangdong, 528400, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, 519000, China; School of Pharmaceutical Sciences, Fudan University, Shanghai, 201203, China. Electronic address: [email protected].
Pancreatic ductal adenocarcinoma (PDAC) is the most malignant tumor with dismal prognosis. The chemotherapy effect of PDAC is limited and has severe side effects. Hence, identifying a natural leading compound with high efficacy against PDAC is urgently needed. Chrysanthemum morifolium (C. morifolium), a traditional Chinese medicinal herb with reported antitumor properties, was hypothesized to contain Polysaccharides with therapeutic efficacy against PDAC. A novel homogeneous RG-I pectin, HJ222, was successfully isolated and purified. Structural analysis shows that HJ222 possesses a backbone composed of repeating →2-α-Rhap-(1 → 4)-α-GalpA-(1 → units, with side chains extending from the O-4 position of 2,4-α-Rhap and certain 3,4-α-GalpA residues, forming galactose- and arabinose-rich branches. In vitro and in vivo assays demonstrate that the sulfated derivative S3HJ222 of HJ222 can significantly suppress pancreatic Cancer cell proliferation and completely retard tumor growth in patient-derived xenograft mouse models. Mechanistic studies reveal that S3HJ222 can induce ferroptosis-a non-apoptotic form of cell death-by elevating intracellular Fe2+ and Reactive Oxygen Species (ROS). Furthermore, S3HJ222 directly binds and stabilizes Transferrin Receptor (TFRC), and activates the acyl-CoA synthetase long-chain family member 4 (ACSL4) signaling axis. Collectively, S3HJ222 may be a promising active compound for the development of new anti-PDAC drugs.