Ferroptosis inhibition by spermidine via the NCOA4/Ferritin axis and polyamine-microbiota dysbiosis in ulcerative colitis.

Spermidine (SPD), a microbiota‑derived polyamine, exerts potent anti‑inflammatory effects in colitis. This study investigated how SPD mitigates dextran sulfate sodium (DSS)-induced ferroptosis and explored the association between gut microbiota composition and polyamine metabolites in patients with ulcerative colitis (UC). DSS‑induced UC models were established in mice and HT‑29 cells, followed by SPD treatment. RNA sequencing was used to profile transcriptomic changes in HT‑29 cells, and the effects of SPD on NCOA4 and Ferritin were evaluated both in vivo and in vitro. NCOA4 silencing was performed to clarify its role in SPD‑mediated protection against ferroptosis. Fecal polyamines and gut microbiota profiles from UC patients and healthy controls were analyzed using UHPLC‑MS/MS and 16S rRNA sequencing. SPD significantly alleviated DSS‑induced colitis. Gene set enrichment analysis (GSEA) of differentially expressed genes in HT‑29 cells highlighted iron‑metabolism pathways as prominently affected. SPD mitigated DSS‑induced ferroptosis in vitro and in vivo, likely by limiting NCOA4‑dependent ferritin turnover and maintaining iron balance. In UC patients, disturbances in fecal polyamine levels corresponded closely with shifts in gut microbial composition, with 27 genera showing significant correlations with polyamine metabolites. Together, these findings position SPD as a modulator of ferroptosis via the NCOA4-ferritin axis and point to a potential therapeutic avenue. In UC, disrupted polyamine metabolites are closely linked to microbial alterations, implicating microbe-polyamine interactions in disease pathogenesis.