Downregulation of Cathepsin B expression alleviates periodontitis by reducing mitochondrial reactive oxygen species production and NOD-, LRR-, and pyrin domain-containing 3 -mediated pyroptosis.

Background: Periodontitis is one of the most common oral inflammatory diseases, and NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated pyroptosis plays a crucial role in its pathogenesis. Cathepsin B (CTSB), a lysosomal cysteine protease, is closely associated with programmed cell death. Our study aimed to investigate the role of CTSB in periodontitis development through the NLRP3-mediated pyroptosis pathway and further explore the mechanism through which CTSB triggers NLRP3 activation. Methods: Ligature-induced periodontitis were established in BALB/c mice. Adeno-associated virus (AAV) was employed to downregulate CTSB expression in periodontal tissues. Small-interfering RNA (siRNA) was used to inhibit CTSB expression in macrophages for Results: CTSB downregulation significantly reduced alveolar bone resorption and macrophage infiltration in periodontitis. Although NLRP3 and inflammatory cytokine levels increased in periodontitis, they were effectively reduced after CTSB inhibition in the periodontal region. Consistent with Conclusions: Inhibiting CTSB expression alleviates periodontitis, primarily by suppressing NLRP3-mediated pyroptosis in macrophages. The mechanism through which CTSB activates NLRP3 likely involves inducing mitochondrial ROS generation. These findings reveal a novel mechanistic axis (CTSB-mitochondrial ROS-NLRP3) in periodontitis, highlighting a potential conceptual target for future therapeutic strategies.