Bacterial meningitis (BM), characterized by bacterial invasion of the meninges and subsequent intense inflammatory response, represents a severe infectious disease of the central nervous system (CNS) [1]. The condition carries a high mortality rate if left untreated, and even with immediate therapeutic intervention, survivors frequently experience devastating long-term neurological sequelae, including hearing loss, developmental delays, and cognitive impairment [2].

BM can be caused by a variety of pathogens with diverse transmission patterns, and the distribution varies by geographic region, age group, and population characteristics [3]. While effective vaccines exist for some common causes such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae, several clinically important pathogens remain without vaccine protection [3]. In Southeast Asia, Streptococcus suis, particularly serotype 2 (SS2), emerges as the most common cause of meningitis, representing a zoonotic threat with animal-to-human transmission in occupational settings [4]. Among neonatal populations, extraintestinal pathogenic Escherichia coli (ExPEC) represents one of the leading causes of BM, typically acquired through environmental contamination or vertical transmission during birth [5]. Both pathogens lack effective vaccines and exhibit increasing antibiotic resistance, making them important targets for investigating novel therapeutic approaches.

The pathogenesis of BM initiates with bacterial traversal across the blood-brain barrier and/or blood-cerebrospinal fluid barrier, facilitating CNS invasion [6,7]. Upon CNS entry, pathogen recognition by resident immune cells, primarily microglia and astrocytes, triggers innate immune responses characterized by robust pro-inflammatory cytokine production. This inflammatory cascade culminates in either systemic complications such as septic shock or localized effects, including leukocyte recruitment and acute CNS inflammation. Moreover, the excessive pro-inflammatory responses disrupt blood-brain barrier integrity through degradation of endothelial tight junction (TJ) proteins, further compromising its integrity and exacerbating the progression of BM [8].

Antibiotic therapy remains the primary treatment of BM, with the selection criteria encompassing patient-specific risk factors, allergic profiles, and local antimicrobial resistance patterns. Third-generation cephalosporins, particularly ceftriaxone, constitute the mainstay of empirical treatment [9]. However, antibiotic-induced bacterial lysis releases damage-associated molecular patterns, perpetuating inflammation and neuronal injury even after bacterial clearance [10]. While adjuvant anti-inflammatory therapies are employed to counteract these effects, the nutrient-poor environment of cerebrospinal fluid promotes bacterial antibiotic tolerance through reduced metabolic activity [11]. These therapeutic challenges underscore the urgent need for novel treatment strategies targeting the pathogenesis of BM.

Extracts from plants have been reported to possess abundant bioactivities [12,13]. Taxifolin (TAX), a plant-derived flavonoid with an established safety profile, has received regulatory approval from the European Food Safety Authority as a dietary supplement [14]. Recent investigations have revealed its diverse biological activities, including remarkable antioxidant capacity exceeding that of quercetin by 100–300 fold [15]. TAX exhibits potent anti-inflammatory properties through modulation of AKT/IKK/NF-κB and MAPK signalling cascades [16] and demonstrates therapeutic potential in Alzheimer’s disease by preserving vascular integrity through inhibition of amyloid β-oligomer formation [17]. Furthermore, TAX possesses broad-spectrum antimicrobial activity against various pathogens, including Staphylococcus epidermidis, Pseudomonas aeruginosa, E. coli, Streptococcus species, Mycobacterium tuberculosis, and fungi [[18], [19], [20]]. Additionally, TAX has demonstrated potential in cancer therapy [21]. Despite these diverse therapeutic properties, the potential efficacy of TAX in BM treatment and its underlying mechanisms remain unexplored.

Here, we investigated the therapeutic potential of TAX in BM using both in vitro and in vivo approaches. We employed SS2 and ExPEC infection models in BV2 and bEnd.3 cell lines to evaluate the protective effects of TAX against bacteria-induced neuroinflammation and endothelial barrier disruption. Through network pharmacology analysis and subsequent in vitro validation, we identified the PI3K/AKT and MAPK signalling pathways as key molecular targets of TAX. Furthermore, using an SS2-induced mouse model of BM, we demonstrated the significant neuroprotective efficacy of TAX, establishing its potential as a therapeutic agent for BM.