Agonism of PIEZO1 prevents aggravated periodontitis with traumatic occlusion via MAPK signaling pathway

Periodontitis is a chronic inflammatory disease causing alveolar bone loss and tooth damage. Traumatic occlusion (TO) exacerbates its progression, although the process is mechanistically unclear. This study investigated the role of the mechanosensitive ion channel PIEZO1 in TO-aggravated periodontal destruction. In a rat model combining periodontitis and TO, PIEZO1 expression decreased, with increased inflammation and impaired osteogenesis. Yoda1 treatment alleviated periodontal inflammation and bone loss, demonstrating its therapeutic potential. <i>In vitro</i>, mechanical stress and lipopolysaccharide (LPS) synergistically downregulated PIEZO1 in human periodontal ligament fibroblasts (hPDLFs), reducing osteogenic potential and elevating pro-inflammatory responses. Transcriptomics identified mitogen-activated protein kinase (MAPK) pathway inhibition as a key downstream effect. Yoda1-mediated activation restored Extracellular Signal-regulated Kinase (ERK), Jun N-terminal Kinase (JNK), and p38 phosphorylation; promoted osteogenesis; and suppressed inflammatory cytokines. Overall, TO exacerbates periodontitis by suppressing PIEZO1-MAPK signaling, and PIEZO1 activation may protect periodontal tissues from mechanical and inflammatory damage.