Bioactive polysaccharides mediate ferroptosis to modulate tumor immunotherapy.

Polysaccharides from diverse origins exhibit notable bioactivities, particularly their capacity to exert antitumor and immune-enhancing effects. Concurrently, ferroptosis emerges as a distinctive form of regulated cell death characterized by iron-dependent lipid peroxidation, potentially influencing the demise of specific tumor cells and organismal homeostasis. Recent scholarly attention has increasingly focused on utilizing polysaccharides to modulate tumor cell ferroptosis and manipulate cellular immune responses. This article provides an in-depth analysis of contemporary research concerning using polysaccharides to augment antitumor immunity and combat malignancies. Central to our discourse is examining the pivotal role of polysaccharides in mediating ferroptosis, bolstering immune surveillance, and elucidating the interplay between polysaccharides and antitumor immunity. Furthermore, a comprehensive synthesis of the multifaceted roles of polysaccharides in antitumor and immunomodulatory contexts is provided. Recent advances in understanding how polysaccharides enhance immune function by inducing ferroptosis cell death are explained. Lastly, unresolved inquiries are outlined, and potential avenues for future research are proposed, focusing on the translational applications of polysaccharides in antitumor immunotherapy.

Structural characterization and ferroptosis-related immunomodulatory of a novel exopolysaccharide isolated from marine fungus Aspergillus medius.

Marine fungal exopolysaccharides play a crucial role in immunoregulation. In this investigation, a novel polysaccharide was extracted from the culture medium of the marine fungus Aspergillus medius SCAU-236. Compositional analysis revealed a structure composed of glucose units with (1,4)-α-D-Glcp, (1,3,4)-ß-D-Glcp, and (1,4,6)-α-D-Glcp, along with side chains of 1-α-D-Glcp linked to carbon 6 of (1,4,6)-α-D-Glcp and carbon 3 of (1,3,4)-ß-D-Glcp. Functional evaluations on RAW264.7 macrophage cells demonstrated Aspergillus medius polysaccharide (ASMP)'s effects on cell proliferation, nitric oxide levels, and the secretion of TNF-α, IL-6, and IL-1ß cytokines. Additionally, metabolomics indicated ASMP's potential to modulate macrophage immune function by impacting key regulatory molecules, including COX-2, iNOS, Nrf2, SLC7A11, GPX4, and ACSL4. The Nrf2/SLC7A11/GPX4 axis and ACSL4 were suggested to be involved in ASMP-induced ferroptosis, leading to increased reactive oxygen species (ROS) levels and lipid peroxidation. These findings propose a unique mechanism by which ASMP exerts immunomodulatory effects through ferroptosis induction, contributing to the understanding of marine-derived compounds in immunomodulation research.

Puerarin Induces Molecular Details of Ferroptosis-Associated Anti-Inflammatory on RAW264.7 Macrophages.

Puerarin is a natural flavonoid with significant anti-inflammatory effects. Recent studies have suggested that ferroptosis may involve puerarin countering inflammation. However, the mechanism of ferroptosis mediated by the anti-inflammatory process of puerarin has not been widely explored. Herein, puerarin at a concentration of 40 µM showed an anti-inflammatory effect on lipopolysaccharide (LPS)-induced macrophages RAW264.7. The analysis of network pharmacology indicated that 51 common targets were enriched in 136 pathways, and most of the pathways were associated with ferroptosis. Subsequently, the analysis of metabolomics obtained 61 differential metabolites that were enriched in 30 metabolic pathways. Furthermore, integrated network pharmacology and metabolomics revealed that puerarin exerted an excellent effect on anti-inflammatory in RAW264.7 via regulating ferroptosis-related arachidonic acid metabolism, tryptophan metabolism, and glutathione metabolism pathways, and metabolites such as 20-hydroxyeicosatetraenoic acid (20-HETE), serotonin, kynurenine, oxidized glutathione (GSSG), gamma-glutamylcysteine and cysteinylglycine were involved. In addition, the possible active binding sites of the potential targeted proteins such as acyl-CoA synthetase long-chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2), arachidonate 15-lipoxygenase (ALOX15) and glutathione peroxidase 4 (GPX4) with puerarin were further revealed by molecular docking. Thus, we suggested that ferroptosis mediated the anti-inflammatory effects of puerarin in macrophages RAW264.7 induced by LPS.

Catechin Mediates Ferroptosis to Exert an Anti-Inflammatory Effect on RAW 264.7 Cells.

Catechin possesses a potential anti-inflammatory activity, but its anti-inflammatory mechanism is still unclear. Herein, the analysis of network pharmacology showed that catechin might mediate ferroptosis on macrophages to exhibit a significant anti-inflammatory effect on RAW264.7. The metabolomics further indicated that catechin might influence ferroptosis by activating two pathways of cysteine and methionine metabolism and glutathione metabolism, and inhibiting the pathway of ferroptosis to promote the reduction of l-methionine-s-oxide and s-glutathionyl-l-cysteine, and the reduction and synthesis of γ-glutamylcysteine. Furthermore, related proteins (MSRA, CDR, GSR and GCL) in three metabolic pathways and ferroptosis-related proteins (GPX4 and SLC7A11) might be relevant to catechin through molecular docking. Thus, we speculate that catechin plays an anti-inflammatory effect through mediating ferroptosis on RAW264.7, which still needs further focus on the detailed molecular mechanism.