From anti-inflammation to pro-resolution: a new paradigm for specialized pro-resolving mediators in regulating neuroinflammation and repair after cerebral ischemia-reperfusion.

Uncontrolled neuroinflammation following cerebral ischemia-reperfusion is a core pathophysiological process driving secondary brain injury and leading to long-term neurological dysfunction. For decades, traditional "anti-inflammatory" strategies targeting the inhibition of key pro-inflammatory pathways have repeatedly failed in clinical translation, compelling a fundamental re-evaluation of the biological nature of inflammation. Inflammation is not a process that passively subsides upon stimulus removal but a dynamic one that requires active "resolution" through endogenous programs to restore tissue homeostasis. Within this precisely regulated program, a family of endogenous lipid mediators derived from polyunsaturated fatty acids-Specialized Pro-resolving Mediators (SPMs)-act as central executors. This review systematically proposes a translational framework for post-stroke inflammation management, shifting from traditional "passive anti-inflammation" to "active pro-resolution." We first delve into the translational challenges and theoretical limitations of conventional anti-inflammatory therapies. Subsequently, we elaborate on the biosynthetic network of SPMs, their major families (lipoxins, resolvins, protectins, and maresins), and their pleiotropic biological functions, including halting neutrophil infiltration, reprogramming macrophage/microglial functions, enhancing the efficiency of apoptotic cell clearance (efferocytosis), and maintaining blood-brain barrier integrity. The central thesis of this review is that a key mechanism underlying the persistent neuropathological deterioration after cerebral ischemia-reperfusion is the failure of the endogenous inflammation resolution program, termed "resolution dysfunction." By integrating mounting clinical evidence with extensive preclinical studies, this review provides a systematic argument for this hypothesis. Exogenous administration of SPMs or their stable analogs has demonstrated significant neuroprotective effects in various animal models, effectively reducing infarct volume and improving functional outcomes. Finally, this review explores the critical challenges in developing SPMs into novel stroke therapies, such as pharmacokinetics, therapeutic windows, and targeted delivery, and poses forward-looking questions for future research in the field. In summary, targeting and restoring the brain's endogenous inflammation resolution programs not only offers a promising new strategy for stroke treatment but also represents a profound practice of a disruptive therapeutic philosophy aimed at promoting the restoration of tissue homeostasis.