A sulfated pectin polysaccharide from Chrysanthemum morifolium induces ferroptosis in pancreatic cancer by stabilizing TFRC.

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.