TRAF6 Lactylation in Glycolytic Macrophages Drives NF‐κB Signaling and M1 Polarization During Orthodontic Tooth Movement

ABSTRACT Protein lactylation is an emerging lactate‐derived modification, coupling metabolic reprogramming to inflammatory regulation while modulating cellular responses to the microenvironment. However, the role of macrophage lactylation in orthodontic tooth movement (OTM) remains unclear. Transcriptomic and metabolomic profiling of compressed macrophages identified glycolytic reprogramming as the core regulatory axis, with elevated lactate levels validated in macrophages, mice, and human saliva. Exogenous lactate promoted M1 polarization and NF‐κB signaling activation in compressed macrophages, identifying lactate dehydrogenase A (LDHA) as a critical regulatory node. Myeloid‐specific Ldha deficiency inhibited OTM and attenuated sterile inflammation, confirming the critical link between lactate metabolism and OTM progression. Mechanistically, we utilized lactylation proteomics and identified that lactate induces specific lactylation of TRAF6 at lysine residues 171, 180, and 388 (K171, K180, K388). Molecular dynamics simulations and site‐directed mutagenesis revealed that K171/K180 lactylation enhances TRAF6 K63‐linked ubiquitination, thereby driving NF‐κB signaling activation. Consistently, mutation of K171 and K180 diminished TRAF6 K63‐linked ubiquitination and suppressed NF‐κB activation. Collectively, our findings demonstrate that sustained compressive force reprograms macrophage metabolism toward glycolysis and drives lactylation of TRAF6 at K171/K180, which serves as a core regulatory node that amplifies NF‐κB signaling, thereby facilitating OTM‐associated sterile inflammation and alveolar bone remodeling.