Tauroursodeoxycholic acid modulates neuroinflammation via STING/NF-κB inhibition after traumatic brain injury.

The incidence of traumatic brain injury (TBI) has demonstrated a marked escalation recently. Nevertheless, there remains a critical paucity of effective drug interventions targeting persistent neuroinflammation-induced damage following TBI. STING/NF-κB axis-induced pyroptosis emerges as a pivotal mechanism driving persistent neuroinflammation, providing it as a potential target for multi-pathway precision therapeutic in TBI. Tauroursodeoxycholic acid (TUDCA), a bile acid endogenously produced primarily in the liver, has been approved by the FDA due to its potential therapeutic properties, particularly hepatoprotective and anti-inflammatory effects. In this study, we discover that TUDCA effectively improves behavioral deficits caused by TBI in vivo. Then, TUDCA attenuates TBI-induced pathology of neuronal injury and inflammation in mice, which involves in signal transduction of the STING pathway and pyroptosis pathway. In vitro, TUDCA inhibits STING and NF-κB/NLRP3 pathways driven neuronal pyroptosis. We find that TUDCA further blocks the nuclear translocation response of IRF3/NF-κB and its activation of downstream transcriptional programs. Mechanistically, TUDCA as a potential STING inhibitor targets the pocket of STING protein. Overall, our results give evidence suggesting that TUDCA serves as a promising therapeutic candidate for TBI, specifically targeting the inflammation mediated damage of neurons.