<p>SUMO1 is involved in the normal physiological functions of the nervous system and is also associated with the development of neurodegenerative diseases. Whereas, the effects and underling mechanisms of SUMO1 knockout (SUMO1- KO) on emotion- and cognition -related behaviors remain unexplored. We investigated changes in depression-like behaviors, social interaction, and cognition in SUMO1-KO mice compared to wild-type (WT) controls using the open-field test, tail suspension test, three-chamber test and novel object recognition test, respectively. To explore the underlying mechanisms of these behavioral differences, we performed Gene Ontology (GO) analysis of proteomics data and subsequently validated the findings through experimental verification. The results showed that SUMO1-KO mice exhibited increased risk-taking behavior, reduced depressive symptoms, and diminished novelty socialization compared to WT mice. Mass spectrometry-based proteomics analysis revealed 370 upregulated proteins and downregulated 84 proteins. GO annotation analysis identified significant enrichment of amino acid transmembrane transporter activities and ion channel. We further investigated two behavior-associated proteins, Hmox1 and Rpgrip1l, and validated their downregulated expression. We concluded that decreased expression of Hmox1 and Rpgrip1l associated with the risk-taking behavior, reduced depressive symptoms, and diminished novelty socialization observed in SUMO1-KO mice.</p> Graphical Abstract <p></p>