Bone infections pose a significant global challenge in orthopedics, often leading to poor bone healing, limb dysfunction, and the need for additional surgeries. Lysine lactylation (Kla) has emerged as a novel post-translational modification, garnering considerable research attention. However, its role in bone infection remains unclear. In this study, results show that Kla levels are significantly higher in the bone tissues of infected patients than in the uninfected controls. Global Kla quantitative proteomics identified 491 Kla sites on 201 proteins, each with distinct expression patterns in bone tissue. Phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme, undergoes lactylation at residue K361. By designing adenoviral vectors that mimic either the lactylated or delactylated forms of this site and employing adeno-associated viruses to specifically target osteoblasts, in vitro and in vivo studies suggest that modifying PGK1 at K361 through Kla may offer a promising strategy for treating infection-induced osteogenic dysfunction. Integrating patient proteomic data further reveals and validates a novel mechanism: PGK1 K361 lactylation activates VDAC3, triggering FtMt/PINK1/Parkin-mediated mitophagy and inducing ferroptosis in osteoblasts. Collectively, these findings provide new mechanistic insights into osteogenic impairment during bone infection and suggest that PGK1 K361 lactylation is a promising intervention target.
Qin et al. (Wed,) studied this question.