〔Abstract〕 Objective To investigate the expression changes of the Endophilin A1 (EPA1)-ROS-NLRP1 signaling pathway in chronic unpredictable mild stress (CUMS)-induced depression model mice. MethodsC57BL/6 mice were randomly divided into control group and CUMS model group. The model mice received 42 days of CUMS stress exposure, after which behavioral changes were assessed through monitoring body weight, sucrose preference test, forced swim test, tail suspension test, open field test, and elevated plus-maze test. Hematoxylin-Eosin and Nissl staining were used to observe neuronal damage in hippocampal CA1 and CA3 regions. Calcium ion (Ca²⁺) assay kit was used to detect Ca²⁺ levels in the hippocampus. Immunofluorescence was used to detect colocalization of EPA1 and NLRP1 as well as ROS changes in the hippocampus. Transmission electron microscopy was used to observe mitochondrial structure in hippocampal neurons. The expression levels of calcium-activated neutral protease 1 (Calpain 1), nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), NLRP1 inflammasome, downstream inflammatory proteins, and synapse-associated proteins in the hippocampus of mice was detected by using Western blot. Results Compared with the control group, mice in the CUMS model group exhibited depressive-like behavior and hippocampal neuronal damage. The levels of NLRP1 and EPA1 significantly increased in the hippocampus, and both were co-expressed in the cytoplasm and membrane of hippocampal neurons in the CUMS group mice（ P<0.01）. Ca²⁺ concentration was elevated（ P<0.01）, and the protein levels of Calpain 1 and NOX2 were upregulated（ P<0.01）. The average fluorescence intensity of ROS significantly increased, accompanied by structural damage to neuronal mitochondria（ P<0.01）; The levels of NLRP1 and its downstream inflammatory proteins significantly increased ( P<0.01), while the expression levels of synapse-associated proteins significantly decreased ( P<0.01). Conclusion EPA1 exhibits abnormal expression changes in CUMS-induced depression model mice, which may be closely associated with ROS generation, NLRP1 inflammasome activation, and the regulation of synaptic protein expression.