Matrine Attenuates Neurological Deficits and Neuroinflammation by Inhibiting the HMGB1 / RAGE Axis and Ferroptosis in Intracerebral Hemorrhage Mice

Intracerebral hemorrhage (ICH) is a life‐threatening stroke subtype that lacks effective drug therapy. In the context of ICH, neuroinflammation, and ferroptosis are key contributors to secondary brain injury. In this study, we assessed the neuroprotective effects of matrine (MAT) and its mechanism of action involving the HMGB1/RAGE axis in an ICH mouse model. ICH was induced in mice by autologous blood injection. MAT (1.5 or 20 mg/kg) was administered orally 5 min postinduction. ICH significantly upregulated RAGE and its associated proteins (HMGB1, protein kinase C [PKC], phospholipase C [PLC], and β‐amyloid), confirming pathway activation. Molecular docking revealed a specific hydrogen bond interaction between MAT and RAGE but not with PKC or PLC. MAT improved neurological performance, reduced hematoma volume and brain edema, and restored blood–brain barrier integrity through upregulation of tight junction proteins (ZO‐1, Occludin, Claudin‐4). MAT suppressed activation of the HMGB1/RAGE pathway and downstream kinases JNK, p38, ERK1/2, and NF‐κB p65. It also decreased IL‐1β, IL‐6, and TNF‐α levels, reduced Bax, increased Bcl‐2, and mitigated neuronal apoptosis. Additionally, MAT lowered Fe 2+ accumulation, inhibited ACSL4, and restored GPX4 levels, indicating ferroptosis suppression. RAGE knockdown mimicked the effects of MAT and negated its therapeutic benefits. MAT induced no detectable liver or kidney toxicity. This study is the first to demonstrate that MAT alleviates ICH‐induced neurological deficits by targeting the HMGB1/RAGE axis‐mediated ferroptosis, thereby extending the current understanding of the neuroprotective mechanisms of MAT beyond its known anti‐inflammatory and antioxidant actions.