Peroxiredoxins in Stroke: Friends and Foes

Stroke, a leading cause of mortality and long-term disability, induces complex cascades of oxidative stress and neuroinflammation that exacerbate brain injury. The peroxiredoxin (Prx; Prdx) family, composed of six thiol-dependent antioxidant enzymes (Prx1-6), plays a pivotal role in regulating redox homeostasis and immune responses in the brain. This review synthesizes current knowledge on the isoform-specific roles of Prxs in both ischemic and hemorrhagic stroke, highlighting their dual and context-dependent functions. Intracellular Prxs generally protect neurons and maintain blood-brain barrier (BBB) integrity, while extracellular Prxs-particularly Prx1 and Prx2-act as damage-associated molecular patterns (DAMPs), activating toll-like receptor signaling and amplifying inflammation. Isoforms such as Prx3 and Prx4 exhibit mitochondrial and endothelial protective effects, respectively, whereas Prx6 demonstrates complex roles influenced by its acidic, Ca²⁺-independent, phospholipase A2 (aiPLA2) activity and cellular localization. We also discuss emerging tools for studying Prx biology and explore the translational potential of Prxs as biomarkers and therapeutic targets. Ultimately, a nuanced understanding of Prx dynamics offers new avenues for stroke diagnosis, prognosis, and treatment.