SPM‐Mediated Macrophage Reprogramming in Periodontal Regeneration: From Resolution Biology to Therapeutic Strategies

<jats:p>Periodontal regeneration requires coordinated control of inflammation, tissue remodeling, vascular responses, and bone turnover. Conventional anti-inflammatory strategies can reduce inflammatory burden but may not restore the active biological programs that terminate inflammation and initiate repair. Specialized pro-resolving mediators (SPMs)—including lipoxins, resolvins, protectins, and maresins—are endogenous lipid mediators that actively promote resolution while preserving host defense. Increasing evidence indicates that macrophages are major cellular targets of SPM activity and that SPM signaling can alter macrophage efferocytosis, phagocytosis, inflammatory mediator production, metabolism, and tissue-remodeling functions. In experimental periodontitis, SPM treatment, particularly Resolvin E1 (RvE1) and lipoxins, has been associated with reduced inflammation and prevention or regeneration of alveolar bone loss. Human studies further suggest that RvE1 can restore impaired macrophage phagocytic activity in periodontal disease. Recent mechanistic work across inflammatory and regenerative models indicates that resolvins can reprogram macrophage metabolism toward oxidative phosphorylation and fatty-acid utilization, enhance efferocytosis, and support tissue repair. In this review, we integrate periodontal, macrophage, lipid-mediator, and regenerative biology to propose an SPM–macrophage framework for periodontal regeneration. We discuss receptor-dependent signaling, immunometabolic reprogramming, efferocytosis, inflammatory shutdown, extracellular-matrix remodeling, angiogenesis, and bone homeostasis as interconnected components of resolution-directed repair. We further evaluate translational opportunities, including local SPM delivery, receptor agonism, biomarker development, and combination with regenerative procedures. Important limitations remain, including the short half-life and analytical challenges of SPMs, heterogeneity among experimental models, and the need to establish causal relationships between macrophage reprogramming and periodontal regeneration. We propose that therapeutically enhancing macrophage resolution capacity may provide a strategy to couple inflammation control with functional periodontal tissue repair.</jats:p>