PI3K-Akt signaling network crosstalk in cerebral ischemia/reperfusion injury: Mechanisms and therapeutic implications.

Abstract

Cerebral ischemia (CI) is an acute central nervous system disorder resulting from the abrupt interruption of blood flow to brain tissue. The restoration of blood flow during treatment is frequently accompanied by cerebral ischemia/reperfusion (CI/R) injury, a secondary injury mechanism that substantially limits the overall efficacy of reperfusion therapy. The phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, a central regulator of cell survival, proliferation, and stress response, has attracted growing interest for its role in CI and CI/R injury. During the early ischemic phase, PI3K-Akt activation in neurons and brain microvascular endothelial cells serves as a crucial endogenous protective mechanism, inhibiting apoptosis and maintaining energy metabolic homeostasis, thereby mitigating initial brain damage. As ischemia progresses, downregulation of this pathway in microglia and infiltrating macrophages can promote excessive release of proinflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), exacerbating local inflammation and tissue injury. In the reperfusion phase, reactivation of the PI3K-Akt pathway exerts multi-level neuroprotection: It counteracts neuronal apoptosis and oxidative stress, promotes angiogenesis and blood-brain barrier (BBB) repair in endothelial cells, and modulates neuroinflammation in glial cells. Importantly, the PI3K-Akt pathway does not function in isolation but engages in complex crosstalk with multiple signaling cascades, such as Wnt/β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), and mammalian target of rapamycin (mTOR). Moreover, it shapes the immune microenvironment by fine-tuning the functions of immune cells, including regulatory T cells (Tregs). This intricate network dynamically governs the survival of the neurovascular unit by regulating mitochondrial function, oxidative stress, inflammation, and autophagy. This review systematically explores the dynamic changes, cell-specific functions, and interactive mechanisms of the PI3K-Akt pathway during CI and CI/R injury, and discusses its potential for precision treatment strategies and clinical translation.

Key Findings

• Activation of the PI3K-Akt signaling pathway during early cerebral ischemia serves as an endogenous protective mechanism by inhibiting apoptosis and maintaining metabolic homeostasis.
• Downregulation of PI3K-Akt in microglia and macrophages during ischemia promotes proinflammatory factor release, exacerbating inflammation and tissue injury.
• Reactivation of PI3K-Akt during reperfusion provides neuroprotection by counteracting apoptosis and oxidative stress, promoting angiogenesis and blood-brain barrier repair, and modulating neuroinflammation.
• PI3K-Akt pathway interacts with multiple signaling cascades including Nrf2/HO-1, influencing mitochondrial function, oxidative stress, inflammation, and autophagy in the neurovascular unit.

Clinical Significance

Citation

Yang Wenzhe, Yang Qian, Wang Zhihuiet al.. PI3K-Akt signaling network crosstalk in cerebral ischemia/reperfusion injury: Mechanisms and therapeutic implications. Chinese medical journal. 2026-Sep-20.