Growing evidence suggests that persistent oral infectious diseases (OIDs) contribute to systemic disease, highlighting the importance of understanding their pathogenic mechanisms. Conventional dental treatments, primarily mechanical debridement, surgical intervention, or antimicrobial therapy, often struggle to fully control inflammation or prevent progressive tissue destruction. The nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome is a key regulator of innate immunity, mediating the maturation of proinflammatory cytokines (IL-1β and IL-18) and the pyroptosis-inducing protein gasdermin D. Dysregulated or excessive activation of NLRP3 contributes to the initiation and progression of major oral diseases, including periodontitis, peri-implantitis, pulpitis, and oral mucosal inflammation. Despite growing interest in NLRP3, comprehensive and up-to-date reviews integrating its pathogenic mechanisms and therapeutic potential remain limited. This review summarizes current and past evidence on the role of the NLRP3 inflammasome in oral disease development, highlights emerging pharmacological strategies, and outlines future research directions. Existing studies demonstrate that microbial components and danger signals from injured tissues activate NLRP3, thereby amplifying inflammation, tissue degradation, and bone resorption. Preclinical studies indicate that inflammasome inhibitors and several natural compounds reduce tissue damage; however, their clinical translation remains limited. These findings emphasize the need for deeper understanding of NLRP3-mediated pathways, with translational and clinical research offering promising therapeutic opportunities for oral diseases.

Rufy4, a protein belonging to the RUN and FYVE domain-containing protein family, participates in various cellular processes such as autophagy and intracellular trafficking. However, its role in osteoclast-mediated bone resorption remains uncertain. In this study, we investigated the expression and role of the Rufy4 gene in osteoclasts using small interfering RNA (siRNA) transfection and gene overexpression systems. Our findings revealed a significant increase in Rufy4 expression during osteoclast differentiation. Silencing Rufy4 enhanced osteoclast differentiation, intracellular cathepsin K levels, and formation of axial protrusive structures but suppressed bone resorption. Conversely, overexpressing wild-type Rufy4 in osteoclasts hindered differentiation while promoting podosome formation and bone resorption. Similarly, overexpression of a Rufy4 variant lacking the RUN domain mimics the effects of Rufy4 knockdown, significantly increasing intracellular cathepsin K levels, promoting osteoclastogenesis, and elongated axial protrusions formation, yet inhibiting bone resorption. These findings indicate that Rufy4 plays a critical role in osteoclast differentiation and bone resorption by regulating the cytoskeletal organization through its RUN domain. Our study provides new insights into the molecular mechanisms governing osteoclast activity and underscores Rufy4’s potential as a novel therapeutic target for bone disorders characterized by excessive bone resorption.

Osteoclasts are bone-resorbing multinucleated giant cells formed by the fusion of monocyte/macrophage lineages. Various small GTPases are involved in the multinucleation and differentiation of osteoclasts. However, the roles of small GTPases regulatory molecules in osteoclast differentiation remain unclear. In the present study, we examined the role of Dennd2c, a putative guanine nucleotide exchange factor for Rab GTPases, in osteoclast differentiation. Knockdown of Dennd2c promoted osteoclast differentiation, resorption, and expression of osteoclast markers. Morphologically, Dennd2c knockdown induced the formation of larger osteoclasts with several protrusions. In contrast, overexpression of Dennd2c inhibited the multinucleation and differentiation of osteoclasts, bone resorption, and the expression of osteoclast markers. Dennd2c-overexpressing macrophages exhibited spindle-shaped mononuclear cells and long thin protrusions. Treatment of Dennd2c-overexpressing cells with the Cdc42 inhibitor ML-141 or the Rac1 inhibitor 6-thio-GTP prevented protrusion formation. Moreover, treatment of Dennd2c-overexpressing cells with the actin polymerization inhibitor latrunculin B restored multinucleated and TRAP-positive osteoclast formation. These results indicate that Dennd2c negatively regulates osteoclast differentiation and multinucleation by modulating protrusion formation in macrophages.

Osteoclasts are the primary bone-resorbing cells responsible for maintaining skeletal homeostasis through balanced bone remodeling. Accumulating evidence suggests that oxidative stress is an emerging regulator of osteoclast differentiation, metabolic reprogramming, and bone resorption, arising from excessive reactive oxygen species (ROS) and insufficient antioxidant defenses. Dysregulated redox signaling contributes to osteoporosis, rheumatoid arthritis, periodontitis, periapical lesions, and other osteolytic disorders. This review summarizes recent advances in the molecular mechanisms linking oxidative stress to osteoclast metabolism, focusing on ROS sources, mitochondrial dysfunction, redox-sensitive signaling pathways, endogenous antioxidant systems, and emerging antioxidant-based therapies. Oxidative stress regulates osteoclastogenesis through interconnected signaling networks, including NF-κB, MAPKs, PI3K/Akt, AMPK, mTOR, NFATc1, and Keap1/Nrf2. Under both physiological and pathological conditions, osteoclast function is regulated by mitochondrial dynamics, mitophagy, and epigenetic mechanisms. Although both synthetic and natural antioxidants have been shown to reduce pathological osteoclast activity in preclinical studies, limitations in bioavailability, target specificity, and long-term efficacy hinder clinical translation. Advances in multi-omics technologies, single-cell analyses, biomarker discovery, precision medicine, and targeted antioxidant delivery may facilitate the development of effective therapies for oxidative stress-related bone disorders.

Osteoclasts are the primary bone-resorbing cells responsible for maintaining skeletal homeostasis through balanced bone remodeling. Accumulating evidence suggests that oxidative stress is an emerging regulator of osteoclast differentiation, metabolic reprogramming, and bone resorption, arising from excessive reactive oxygen species (ROS) and insufficient antioxidant defenses. Dysregulated redox signaling contributes to osteoporosis, rheumatoid arthritis, periodontitis, periapical lesions, and other osteolytic disorders. This review summarizes recent advances in the molecular mechanisms linking oxidative stress to osteoclast metabolism, focusing on ROS sources, mitochondrial dysfunction, redox-sensitive signaling pathways, endogenous antioxidant systems, and emerging antioxidant-based therapies. Oxidative stress regulates osteoclastogenesis through interconnected signaling networks, including NF-κB, MAPKs, PI3K/Akt, AMPK, mTOR, NFATc1, and Keap1/Nrf2. Under both physiological and pathological conditions, osteoclast function is regulated by mitochondrial dynamics, mitophagy, and epigenetic mechanisms. Although both synthetic and natural antioxidants have been shown to reduce pathological osteoclast activity in preclinical studies, limitations in bioavailability, target specificity, and long-term efficacy hinder clinical translation. Advances in multi-omics technologies, single-cell analyses, biomarker discovery, precision medicine, and targeted antioxidant delivery may facilitate the development of effective therapies for oxidative stress–related bone disorders.