〔Abstract〕 Objective To elucidate the molecular mechanism of receptor for advanced glycation end products(RAGE) inhibitor FPS-ZM1 in the treatment of depression in db/db mice. Methods 24 male db/db mice aged 6-8 weeks were randomly divided into type 2 diabetic group(db/db group), diabetic treatment group [db/db+FPS, FPS-ZM1 1.0 mg/(kg·d) was administered intraperitoneally] and diabetic solvent control group(db/db+Oil, mice were injected intraperitoneally corn oil with the same volume). The other 8 male db/m mice aged the same weeks were used as normal control. After administrating drugs for 12 weeks, the depression-like behavior of mice was detected by tail suspension and forced swimming test, the apoptosis of neurons in mice hippocampus was detected by TUNEL staining, and the expression of RAGE, nod-like receptor protein 3(NLRP3), interleukin-1β(IL-1β) and cysteinyl aspartate specific proteinase-1(Caspase-1) in mice hippocampus was detected by Western blot. Results In behavioral experiments db/db mice showed depressive symptoms, which could be improved by FPS-ZM1. Compared with db/m mice, the apoptosis rate of hippocampal neurons in db/db mice was significantly higher(P<0.01), which could also be significantly reduced by FPS-ZM1(P<0.01). The expressions of RAGE, NLRP3, IL-1β and Caspase-1 in the hippocampus of db/db mice were significantly higher than those of db/m mice(P<0.01) and FPS-ZM1 could still inhibit the expression of these proteins. Conclusion FPS-ZM1 can reduce the apoptosis of hippocampal neurons by inhibiting RAGE and its downstream NLRP3 signal pathway, and eventually improve the depressive symptoms of diabetic mice.