DJ-1 is a multifunctional protein associated with cancers and autosomal early-onset Parkinson disease.Besides the well-documented antioxidative stress activity,recent studies show that DJ-1 has deglycation enzymatic activity and anti-ferroptosis effect.It has been shown that DJ-1 forms the homodimerization,which dictates its antioxidative stress activity.In this study,we investigated the relationship between the dimeric structure of DJ-1 and its newly reported activities.In HEK293T cells with Flag-tagged and Myc-tagged DJ-1 overexpression,we performed deletion mutations and point mutations,narrowed down the most critical motif at the C terminus.We found that the deletion mutation of the last three amino acids at the C terminus of DJ-1(DJ-1ΔC3)disrupted its homodimerization with the hydrophobic L187 residue being of great importance for DJ-1 homodimerization.In addition,the ability in methylglyoxal(MGO)detoxification and deglycation was almost abolished in the mutation of DJ-1 ΔC3 and point mutant L187E compared with wild-type DJ-1(DJ-1 WT).We also showed the suppression of erastin-triggered ferroptosis in DJ-1-/-mouse embryonic fibroblast cells was abolished by ΔC3 and L187E,but partially diminished by V51C.Thus,our results demonstrate that the C terminus of DJ-1 is crucial for its homodimerization,deglycation activity,and suppression of ferroptosis.