Abstract
Specialized pro-resolving mediators (SPMs) derived from docosahexaenoic acid (DHA), particularly D-series resolvins (RvD1, RvD2, RvD3, and RvD5), function to terminate inflammation while preserving host defense. They are synthesized from DHA by lipoxygenases and act through G‑protein‑coupled receptors and lipid‑sensing transcription factors (TFs). These mediators reprogram macrophage metabolism towards fatty‑acid oxidation and oxidative phosphorylation, accelerate efferocytosis, and promote tissue repair. Here, we synthesize current knowledge on their biosynthesis, receptor signaling, and immunometabolic rewiring within macrophages, and critically appraise their therapeutic potential across cardiometabolic, musculoskeletal, autoimmune, and ischemia/reperfusion disorders. We also discuss analytical controversies surrounding their in vivo low‑abundance detection, and outline translational challenges including short half‑life, formulation stability, and emerging synthetic agonists. Finally, we propose priority research directions, from single-cell spatial lipidomics to clinical translation, to define the next frontier for resolvin-based immunotherapies.