Quercetin inhibits microglial pyroptosis following intracerebral hemorrhage via the TLR2/MyD88/NF-κB signaling pathway

Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and limited therapies. Pyroptosis, a pro-inflammatory programmed cell death process, contributes critically to secondary brain injury (SBI) following ICH. This study aimed to identify pyroptosis-targeting therapeutic compounds and assess their protective effects in ICH. Pyroptosis-related characteristic differentially expressed ICH-related genes (DEICHRGs) were identified using bioinformatics and network pharmacology, leading to the screening of hub genes. Quercetin (Qu) was predicted as a key active component. Molecular docking was conducted between Qu and hub genes, and Toll-like Receptor 2 (TLR2) was selected as a central regulatory target. In vivo and in vitro experiments were performed to assess the effects of Qu on neurological outcomes, microglial activation/polarization, and Pyroptosis signaling. Qu ameliorated neurological deficits, reduced neuronal loss in perihematomal regions, and modulated microglial activation by suppressing pro-inflammatory phenotype and promoting anti-inflammatory polarization, and downregulated pyroptosis-associated proteins, including NOD-like Receptor pyrin domain-containing protein 3 (NLRP3), cleaved Caspase-1 (CASP1), interleukin-1β (IL-1β), interleukin-18 (IL-18), and cleaved N-terminal Gasdermin D (GSDMD-N). In an oxyhemoglobin-induced BV2 cell model, Qu suppressed the TLR2/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappaB (NF-κB) pathway, thereby inhibiting NLRP3 inflammasome activation and Pyroptosis. This inhibitory effect was reversed by a TLR2/1 agonist, confirming pathway specificity. Qu curbs microglial Pyroptosis after ICH and exerts neuroprotective effects through the TLR2/MyD88/NF-κB signaling pathway.

Bioinformatics; Intracerebral hemorrhage; Network pharmacology; Neurological deficit; Pyroptosis; Quercetin.