The pathogenesis of rheumatoid arthritis (RA) involves a variety of cellular and molecular signaling pathways. TMEM132C and LIPE, as potential key protein molecules, may play an important role in synovial hyperplasia of RA. The main objective of this study was to reveal the function of TMEM132C and LIPE in the proliferation of RA synovial cells, and to explore the mechanism of their regulation through the PPARγ signaling axis. In this study, differential expression genes (DEGs) were screened through data acquisition and preprocessing. Then, principal component analysis (PCA) and functional enrichment analysis were used to clarify the importance of PPARγ signal axis in RA. Then, machine learning technology was used to identify key proteins, and SHAP-driven analysis was used to interpret the results of Logistic regression model. The expression and signaling activities of TMEM132C and LIPE were verified by cell culture, transfection, proliferation detection, RNA extraction, real-time quantitative fluorescence PCR (qPCR) and Western blot experiments. A series of significant DEGs were identified, and functional enrichment analysis showed that the PPARγ signal axis plays a key role in RA. TMEM132C and LIPE were identified as key genes mainly enriched in the PPAR signaling pathway, suggesting that they play an important role in the pathogenesis of RA.