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Women are more likely than men to develop the chronic, progressive autoimmune disease known as rheumatoid arthritis (RA). Although there may be a complex interplay between sex-based differences and autoimmune dysfunction. Their function in RA is largely unknown, though. The purpose of this study was to pinpoint the crucial genes and metabolic pathways that control biological variations in RA between men and women.First, the Gene Expression Omnibus database's gene expression information for GSE39340 and GSE55457 was downloaded (GEO). R software was used to find each of the individually identified differentially expressed genes (DEGs) between the sexes. DEGs that overlapped were found. The interactions between the overlapping DEGs were then further examined using a protein-protein interaction (PPI) network. The Kyoto Encyclopedia of Genes and Genomes and Gene Ontology tools, respectively, were used to perform enrichment analyses.According to our findings, there were 1169 DEGs that overlapped between RA males and females, comprising 845 up-regulated genes and 324 down-regulated genes. Ten hub genes, including PIK3R1, RAC1, HRAS, PTPN11, UQCRB, NDUFV1, EGF, UBA1, UBE2G1, and UBE2E1, were discovered in the PPI network. According to a functional enrichment analysis, these genes were primarily enriched in neurodegenerative illnesses, including various disease pathways, MAPK signaling, insulin signaling, and autophagy.The current data point to the possibility that the MAPK pathway and autophagy may be significant contributors to sex differences in RA. PTPN11, EGF, and UBA1 may be important genes linked to the gender development of RA and are anticipated to be therapeutic targets for the disease. Key Points • Our research point to the possibility that the MAPK pathway and autophagy may be significant contributors to sex differences in RA. • PTPN11, EGF, and UBA1 may be important genes linked to the gender development of RA and are anticipated to be therapeutic targets for the disease. • These findings may aid in the development of novel diagnostic and treatment techniques for RA in men and women.