Sonic Hedgehog pathway: molecular mechanisms and therapeutic potentials in ischemic stroke recovery.

Ischemic stroke (IS) is a leading cause of global mortality and disability, characterized by restricted cerebral blood flow and subsequent neuronal damage. The Sonic Hedgehog (Shh) signaling pathway plays a pivotal role in the pathogenesis and recovery of IS by modulating neuroprotection, angiogenesis, blood-brain barrier (BBB) integrity, and neurogenesis. This review provides an updated analysis of the Shh pathway's molecular mechanisms, emphasizing its neuroprotective effects, including anti-apoptotic, anti-inflammatory, and antioxidant responses. At the cellular level, the Shh pathway supports neuronal survival, enhances synaptic health, promotes M2 microglial polarization, and facilitates astrocyte proliferation, all of which contribute to reducing ischemic damage and fostering tissue repair. Additionally, the pathway's role in regulating endothelial integrity and promoting neurogenesis underscores its therapeutic potential. Pharmacological agents, natural compounds, and advanced therapeutic strategies such as stem cell therapies and nanoparticles targeting the Shh pathway demonstrate significant potential for improving functional outcomes post-stroke. This review identifies critical gaps in understanding the Shh pathway's regulatory dynamics and highlights future directions for therapeutic interventions aimed at leveraging its neuroprotective potential in ischemic stroke recovery.