TFAP2A transcriptionally regulates B3GALT2 to affect gouty arthritis progression through pyroptosis: a study based on machine learning and multi-omics integration analysis.

BACKGROUND: Gouty arthritis (GA) is an inflammatory joint disease driven by monosodium urate (MSU) crystal deposition. The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome-mediated pyroptosis is central to GA pathogenesis, yet potential regulatory targets remain limited. The role of β-1,3-galactosyltransferase 2 (B3GALT2), a glycosyltransferase, is entirely unknown in GA. This study aims to identify novel biomarkers for GA and investigate the role and regulatory mechanism of B3GALT2. METHODS: Differentially expressed genes (DEGs) analysis was performed on the GSE160170 dataset. Machine learning algorithms, including least absolute shrinkage and selection operator (LASSO) regression and random forest (RF), were applied to identify key candidate genes. B3GALT2 expression and its diagnostic value were validated in clinical peripheral blood samples from GA patients and healthy controls. In vitro GA models were established using THP-1 cells stimulated with lipopolysaccharide (LPS) and MSU. Gain- and loss-of-function experiments assessed the effects of B3GALT2 and transcription factor activator protein-2 A (TFAP2A) on pyroptosis. Chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays were used to verify the transcriptional regulation of B3GALT2 by TFAP2A. RESULTS: B3GALT2 was identified as a key down-regulated gene in GA through integrated bioinformatics and machine learning. Clinically, B3GALT2 expression was significantly decreased in GA patients, showed high diagnostic accuracy, and was negatively correlated with inflammatory markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin-6 (IL-6). Functionally, B3GALT2 overexpression in LPS/MSU-induced cell models inhibited NLRP3 inflammasome activation (reducing NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase1 p20) and pyroptosis (decreasing N-terminal gasdermin-D (GSDMD-N), lactate dehydrogenase (LDH) release, and IL-1β/IL-18 secretion). Mechanistically, TFAP2A was predicted and experimentally confirmed to bind directly to the B3GALT2 promoter, activating its transcription. Importantly, the anti-pyroptotic effects of TFAP2A overexpression were largely abolished upon B3GALT2 knockdown. CONCLUSION: This study identifies B3GALT2 as a promising diagnostic biomarker for GA and further reveals a novel TFAP2A/B3GALT2 axis that plays a critical protective role in GA by suppressing NLRP3 inflammasome-mediated pyroptosis. These findings provide new insights into GA pathogenesis and highlight potential therapeutic targets.