Lipid Metabolic Reprogramming in Periodontitis-Associated Alveolar Bone Remodeling: Mechanisms, Signaling Pathways, and Therapeutic Implications.

Periodontitis-associated alveolar bone loss reflects not only persistent inflammation but also profound metabolic remodeling within the periodontal microenvironment. This review synthesizes current evidence on how lipid metabolic reprogramming regulates periodontal bone remodeling and its therapeutic significance. Under physiological conditions, fatty acid uptake and β-oxidation, lipid droplet turnover, and lipid-derived signaling support osteoblast bioenergetics, stem-cell osteogenesis, and balanced bone remodeling. In contrast, dyslipidemia and chronic inflammatory stress promote the accumulation of free fatty acids, oxidized lipoproteins, cholesterol derivatives, and sphingolipid metabolites, thereby enhancing reactive oxygen species production, lipid peroxidation, inflammasome activation, and pro-inflammatory immune polarization. These changes suppress osteogenic differentiation, stimulate osteoclastogenesis, and impair periodontal regeneration. We further integrate major regulatory networks, including PPARγ-Wnt/β-catenin, AMPK-mTOR, NF-κB/NLRP3, and GSK3β-NRF2/ferroptosis signaling. Therapeutic strategies targeting these lipid-redox-immune circuits include specialized pro-resolving lipid mediators, n-3 polyunsaturated fatty acids, statins, metabolic modulators, and local biomaterial- or nanocarrier-based delivery systems. Accordingly, lipid metabolic reprogramming may provide a framework for developing metabolism-oriented adjunctive and regenerative strategies for periodontitis.