Abstract

Background Intracerebral hemorrhage (ICH) is a devastating stroke subtype without effective therapy. Neuroinflammation, particularly driven by NLRP3 inflammasome–mediated pyroptosis, is a key contributor to secondary brain injury (SBI). Ginsenoside Rg2 (Rg2), a natural saponin with anti-inflammatory activity, has been reported to inhibit NLRP3, but its efficacy and mechanisms in ICH remain unclear. Methods In a collagenase-induced ICH mouse model, we evaluated the effects of Rg2 on neurological function, cerebral blood flow, hematoma expansion, neuronal injury, and inflammation. Mechanistic studies included RNA sequencing, western blotting, immunostaining, co-treatment with MCC950, and microglial depletion with PLX3397. Serum NLRP3 levels were analyzed in patients with ICH. Results Rg2 improved acute and long-term neurological and cognitive recovery, restored cerebral blood flow, reduced hematoma expansion, and alleviated neuronal damage. It suppressed central and peripheral inflammation, limiting microglial and astrocytic overactivation. Mechanistically, Rg2 directly targeted NLRP3 to selectively inhibit NLRP3 inflammasome activation and pyroptosis while sparing NLRC4 and AIM2. Partial microglial depletion abolished its benefit, and MCC950 co-treatment produced no additive effect. Serum NLRP3 levels correlated with ICH severity and were reduced by Rg2. Long-term treatment showed no organ toxicity. Conclusions Rg2 confers robust neuroprotection against ICH by selectively targeting NLRP3-mediated pyroptosis, offering both acute and long-term benefits. These findings support Rg2 as a promising candidate for ICH and potentially for other NLRP3-related neuroinflammatory diseases.