Peroxiredoxin 1-Toll-like receptor 4-p65 axis inhibits receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation

Peroxiredoxin 1 (PRDX1), an intracellular antioxidant enzyme, has emerged as a regulator of inflammatory responses via Toll-like receptor 4 (TLR4) signaling. Despite this, the mechanistic details of the PRDX1-TLR4 axis and its impact on osteoclast differentiation remain elusive. Here, we show that PRDX1 suppresses RANKL-induced osteoclast differentiation. Utilizing pharmacological inhibitors, we reveal that PRDX1 inhibits osteoclastogenesis through both TLR4/TRIF and TLR4/MyD88 pathways. Transcriptome analysis revealed PRDX1-mediated alterations in gene expression, particularly upregulating serum amyloid A3 (Saa3) and aconitate decarboxylase 1 (Acod1). Mechanistically, PRDX1-TLR4 signaling activates p65, promoting Saa3 and Acod1 expression while inhibiting Nfatc1, a master regulator of osteoclastogenesis. Remarkably, PRDX1 redirects p65 binding from Nfatc1 to Saa3 and Acod1 promoters, thereby suppressing osteoclast formation. Structural analysis showed that a monomeric PRDX1 mutant with enhanced TLR4 binding exhibited the potent inhibition of osteoclast differentiation. These findings reveal the PRDX1-TLR4 axis's role in inhibiting osteoclastogenesis, offering potential therapeutic insights for bone disorders.