Combination of Xingnaojing injection and acupuncture ameliorate traumatic brain injury by promoting M2 polarization of microglia through KAT2A-mediated HMGB1 succinylation

BACKGROUND: Traumatic brain injury (TBI) remains a leading global cause of morbidity and mortality. Xingnaojing injection (XNJI) and acupuncture, two traditional Chinese medicine (TCM) modalities, are widely utilized in treating various neurological disorders, including TBI. OBJECTIVE: This study aimed to investigate the potential therapeutic mechanism of combined XNJI and acupuncture treatment for TBI, with a focus on the modulation of microglial polarization and the succinylation pathway. METHODS: A rat TBI model was established using a controlled cortical impact (CCI) device. Rats were randomly assigned to five groups. Treatment commenced 24 hours post-TBI and continued for 14 days. Neurological behavioral functions were assessed at multiple time points. Additionally, M1/M2 polarization of microglia was evaluated by measuring polarization-related markers. RESULTS: The combination of XNJI and acupuncture exhibited a synergistic therapeutic effect on TBI, as demonstrated by improved neurological function, reduced tissue damage and edema, modulated inflammatory response, and enhanced activity of the succinylation pathway. Both XNJI and acupuncture individually significantly decreased KAT2A levels, and their combination led to a further significant reduction. Elevated HMGB1 was found to significantly reverse the effects of KAT2A down-regulation on the activation of anti-inflammatory microglia. CONCLUSION: Combined XNJI and acupuncture therapy may represent a novel and effective therapeutic strategy for TBI patients, potentially by promoting M2 microglial polarization via KAT2A-mediated succinylation of HMGB1.