Yang Tian, Shuoyao Ma, Bo Yang, Fei Gao, Hao Guo, Haixiao Liu, Xun Wu, Wenxing Cui, Jingyu Dong, Qian Lin, Yufeng Ge, Jin Ma, Jiazhen Zhao, Yongzhi Zhang, Dongzhi Xue, Jiaxin Tian, Ziwen Zhang, Kai Wang, Meng Xu, Dayun Feng, Jinpeng Zhou, Yan Qu
Traumatic brain injury (TBI) induces brain tissue ischemia, hypoxia, and heightened glycolysis, leading to lactate accumulation. Lactate exerts multiple pathophysiological effects in the aftermath of TBI. This study aimed to elucidate the role of lactate-mediated lactylation in these post-TBI pathological processes. Here, we found that the level of lactylation was elevated in brain tissues after TBI and predominantly in neurons. Proteomic analysis revealed that mitochondrial proteins underwent significant lactylation. Lactylation at the K112 site of fumarate hydratase (FH) induced mitochondrial damage and tricarboxylic acid (TCA) cycle dysfunction. Accumulation of fumarate and release of mitochondrial DNA (mtDNA) activated the cGAS-STING pathway of the innate immune response, thereby exacerbating neuroinflammation and cerebral edema. Furthermore, AARS2 and SIRT3 were identified as the respective "writer" and "eraser" of FH K112 lactylation. The short peptide Pep-K112 targeted and inhibited lactylation at the FH K112 site, ameliorating mitochondrial function and alleviating neuroinflammation and cerebral edema. These findings demonstrate the regulatory role of lactylation in the pathological progression of TBI and suggest that targeting FH lactylation may be a promising strategy for TBI treatment.