Multifaceted mechanisms of 4-hydroxybenzaldehyde in reducing hemorrhagic transformation in ischemic stroke...

The PI3K-AKT signaling pathway has emerged as a central modulator in the pathophysiology of hemorrhagic transformation (HT). Gastrodia elata Blume, a classic neuroprotective herb used in Traditional Chinese Medicine, traditionally believed to "calm endogenous wind" and "unblock meridians". Although phenolic compounds are recognized as key neuroprotective constituents, their anti-hemorrhagic mechanisms remain. This study aimed to validate 4-hydroxybenzaldehyde (4-HBd), a major phenolic component of G. elata, as a therapeutic candidate against ischemic stroke (IS)-associated HT, with a focus on its modulation of PI3K-AKT signaling.

A rat model of transient middle cerebral artery occlusion with induced HT (tMCAO-HT) was established and treated with 4-HBd (20 mg/kg) for assessment of intracerebral hemorrhage and neurological function. Integrated transcriptomic and metabolomic profiling identified 214 differentially expressed genes and 38 differential metabolites. Molecular docking simulations evaluated 4-HBd binding to PI3K and AKT, and in vitro validation was performed in hypoxia-exposed PC12 cells using viability assays and western blot analysis.

4-HBd administration significantly attenuated cerebral hemorrhage (P < 0.01) and improved neurological function (P < 0.01). Multi-omics analysis revealed convergent enrichment of the PI3K-AKT pathway (KEGG: hsa04151), supported by high-affinity docking to both PI3K (ΔG = -5.7 kcal/mol) and AKT (ΔG = -5.3 kcal/mol). Treatment enhanced p-PI3K and p-AKT expression (P < 0.01), rescuing PC12 cells viability under hypoxic conditions (P < 0.05).

4-HBd exerts protective effects against HT by restoring PI3K-AKT signaling.