Background <p>Podocytes are identified as main injury targets in the pathogenesis of hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN). NLR family pyrin domain containing 3 (NLRP3) has a critical function in ​inducing podocyte injury across multiple renal pathologies. This study aimed to explore whether NLRP3 expression linked to podocyte injury participated in the pathogenic mechanism of HBV-GN.</p> Methods <p>The expression of NLRP3, CD68, ‌intercellular cell adhesion molecule-1 (‌ICAM-1), and α-smooth muscle actin (α-SMA) was identified in HBV-GN renal biopsies. The correlations between renal NLRP3 expression and clinical parameters, as well as between HBV X (HBx) expression and inflammation and fibrosis markers, were analyzed. HBx-encoding plasmids were transferred into cultured human podocytes. The downstream targets of HBx determined by RNA-sequencing. The expression of NLRP3 and α-SMA was quantified by western blot analysis. The expression of CD68 was detected using immunofluorescence and flow cytometry. Inflammatory factor levels were examined via ELISA.</p> Results <p>NLRP3 exhibited a remarkable increase in the podocytes of HBV-GN patients, and its expression showed a significant association with proteinuria levels. Furthermore, co-localization of NLRP3 and CD68 was observed within the podocytes of HBV-GN patients. In vitro, HBx markedly upregulated NLRP3 and induced podocyte-macrophage transdifferentiation (PMT) in human podocytes, thereby contributing to the inflammatory reaction and fibrosis. Further analysis indicated that the NLRP3 inhibitor tranilast (TR) attenuated HBx-induced PMT, inflammation and fibrosis.</p> Conclusion <p>These findings indicate that HBx triggers NLRP3 upregulation in podocytes and activates PMT. Thereafter, podocytes may function as antigen-presenting cells (APCs), consequently stimulating immune cell activation and resulting in inflammation cascades and renal fibrosis associated with HBV-GN.</p>