Baicalein attenuates sepsis-associated encephalopathy by inhibiting ASK1-JNK and NF-κB pathways

Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis characterized by neuroinflammation and neurological dysfunction, with limited effective therapies. Baicalein, a major flavonoid derived from Scutellaria baicalensis, exhibits anti-inflammatory and neuroprotective properties, but its role in SAE remains unclear.

Network pharmacology was applied to identify potential targets and signaling pathways of Scutellaria baicalensis in SAE, followed by protein-protein interaction analysis and GO and KEGG enrichment. An LPS-induced SAE mouse model was used to validate the neuroprotective effects of baicalein through assessment of inflammatory cytokines, signaling pathway activation, neurological function, and survival.

Network analysis identified 71 core targets of Scutellaria baicalensis, including 6 core target genes: TNF, IL6, AKT1, JUN, PTGS2, and TP53. Given that JUN and pro-inflammatory cytokines are canonical downstream effectors of stress-activated kinases and NF-κB signaling, subsequent experimental validation focused on the ASK1-JNK and NF-κB pathways, which play central roles in oxidative stress and neuroinflammation associated with sepsis-associated encephalopathy. In vivo, baicalein significantly reduced hippocampal TNF-α and IL-6 levels, compared with the LPS group. Baicalein suppressed activation of the ASK1-JNK and NF-κB pathways, improved cognitive performance, and increased survival rate in SAE mice.

Baicalein alleviated SAE through coordinated anti-inflammatory and neuroprotective effects by modulating stress- and inflammation-related signaling pathways, supporting its potential as a therapeutic candidate for SAE.