Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
Sanggil Kim
Department of Lead Optimization, New Drug Development Center, Osong Medical Innovation Foundation (KBio), 123 Osongsaengmyeng-ro, Cheongju, Chungbuk, Republic of Korea
Hye-Yeon Jung
Korea Basic Science Institute, Gwangju Center at Chonnam National University, Gwangju, Republic of Korea
Eun Hwan Bae
Department of Microbiology, College of Medicine, Inha University, Incheon, Republic of Korea
Minhye Shin
Department of Microbiology, College of Medicine, Inha University, Incheon, Republic of Korea
Jae-Il Park
Korea Basic Science Institute, Gwangju Center at Chonnam National University, Gwangju, Republic of Korea
So-Young Choi
Department of Lead Optimization, New Drug Development Center, Osong Medical Innovation Foundation (KBio), 123 Osongsaengmyeng-ro, Cheongju, Chungbuk, Republic of Korea
Sun-Ju Yi
Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea; Corresponding author
Kyunghwan Kim
Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea; Corresponding author
Summary: 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.
