In a DSS-induced colitis model, we observed that activation of the HMGB1/TLR4/NF-kB pathway resulted in decreased GPX4 expression, accompanied by increased mRNA levels of ferroptosis-related indicators (PTGS2, IREB2, CS, RPL8, and ATP5G3), which was further verified by cellular experiments. The gene discussed is TLR4; the disease is colitis.