a sulfated polysaccharide from Gracilaria lemaneiformis and its potentiation of cisplatin antitumor activity in Colon-26 carcinoma tumor-bearing mice by inducing ferroptosis

Ferroptosis, a form of regulated cell death caused by iron-mediated lipid peroxidation, has become a potential strategy to overcome drug resistance and improve the efficacy of traditional cancer treatments. In this study, we investigated whether treatment with the combination of Gracilaria lemaneiformis polysaccharides and cisplatin (CP) potentiated the antitumor activity in a Colon-26 carcinoma tumor-bearing mouse model by ferroptosis activation. Compared with the CP group, the combination of GP90 and CP significantly suppressed tumor growth. RNA sequencing and metabolite analysis of the tumor tissue were performed to identify potential causal genes and metabolites. At the transcription level, different genes associated with the induction of ferroptosis were identified, and pathway enrichment analysis identified the ferroptosis pathway as a promising target. Subsequently, changes in ferroptosis-related upstream and downstream metabolic pathways, such as glutamate metabolism, glutathione metabolism, and coenzyme A biosynthesis were explored by metabolomic analysis. Four differentially accumulated metabolites were identified, L-glutathione (reduced) was downregulated, and L-glutamic acid, 17(S)-HpDHA, and 16(r)-HETE were upregulated. Moreover, the accumulation of 4-Hydroxy-2-nonanal (4-HNE) and down-regulation of the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (Gpx4) were verified by immunohistochemistry staining. Finally, gene set enrichment analysis showed that positive immunoregulatory pathways were significantly enriched in the GP90 and CP combination group. Our results indicate that GP90 potentiates chemotherapy sensitivity by targeting transferrin receptor and SLC7A11/Gpx4 pathway to induce ferroptosis, which might be useful therapeutic target in colorectal cancer patients.