Specialized pro-resolving mediators in myocardial infarction: orchestrators of inflammation resolution and tissue repair

Myocardial infarction (MI) remains a leading cause of morbidity and mortality wordwide. Despite reperfusion therapies have improved survival, persistent and dysregulated inflammation contributes to adverse remodeling and progression to heart failure. However, the mechanisms by which inflammation is actively terminated and converted into a reparative program in the infarcted heart have not been fully elucidated. Specialized pro-resolving mediators (SPMs)—including lipoxins, resolvins, protectins and maresins—represent a unique class of lipid-derived mediators that regulate the active resolution of inflammation without broadly suppressing host immune defenses like conventional anti-inflammatory drugs. Emerging evidence demonstrates that SPMs can regulate neutrophil clearance, promote efferocytosis, modulate endothelial activation and reprogram cardiac macrophages toward a reparative phenotype. Notably, SPMs signaling interracts with multiple cores signaling networks involved in MI pathology, including the NF-κB, AMPK, Hippo-YAP and JAK/STAT pathways, linking metabolic states and inflammatory signals to structural repair processes. Despite these advances, critical gaps remain regarding the temporal dynamics of SPM biosynthesis after MI, their mechanistic interactions with existing standard therapies, and their clinical translation as biomarkers or therapeutic agents. This review integrates the latest mechanistic and clinical evidence to propose a spatiotemporal specific SPMs-driven cardiac repair framework and highlights how targeting endogenous resolution pathways may complement current MI management. By dissecting key molecular nodes within SPMs signaling, we propose a therapeutic strategy that extend beyond “inflammation suppression” to actively restoring myocardial homeostasis.