Melanin Nanoparticles Alleviates Thalamic Stroke Damage by Modulating Glial Activation and Neuroinflammation

Thalamic strokes represent a major cause of post-stroke cognitive impairment, characterized by glial activation and disrupted iron homeostasis. Microglia and astrocytes play pivotal roles in the inflammatory response, but the mechanisms connecting glial activation to ferroptotic cell death remain unclear. This study explores the neuroprotective effects of melanin nanoparticles (MMPP) in thalamic stroke, focusing on glial activation and neuronal ferroptosis. Using a photothrombotic stroke model, MMPP nanoparticles suppress microglial activation, which subsequently mitigates astrocytic reactivity. Transcriptomic analysis reveals that MMPP nanoparticles regulate the MKK4/JNK signaling pathway, linking glial activation to ferroptosis. Reactive astrocytes secrete lipocalin-2 (LCN2), which triggers ferroptosis in neurons through the 24p3 receptor, causing iron accumulation and ROS production. Additionally, MMPP restores key ferroptosis markers by upregulating GPX4 and downregulating PTGS2, interrupting the pathological cascade, preserving neuronal antioxidant defenses, and reducing ferroptotic cell death. These findings highlight MMPP’s dual antioxidant and anti-inflammatory effects, particularly through modulation of the microglia-astrocyte-LCN2 axis. This study suggests that MMPP provides a promising therapeutic strategy to alleviate neuroinflammation and promote functional recovery following ischemic stroke.