Mitochondrial dysfunction and oxidative injury, which contribute to worsening of neurological deficits and poor clinical outcomes, are hallmarks of secondary brain injury after TBI. Adiponectin (APN), beyond its well-established regulatory effects on metabolism, is also essential for maintaining normal brain functions by binding APN receptors that are ubiquitously expressed in the brain. Currently, the significance of the APN/APN receptor (AdipoR) signaling pathway in secondary injury after TBI and the specific mechanisms have not been conclusively determined. In this study, we found that APN knockout aggravated brain functional deficits, increased brain edema and lesion volume, and exacerbated oxidative stress as well as apoptosis after TBI. These effects were significantly alleviated after APN receptor agonist (AdipoRon) treatment. Moreover, we found that AdipoR1, rather than AdipoR2, mediated the protective effects of APN/AdipoR signaling against oxidative stress and brain injury after TBI. In neuron-specific AdipoR1 knockout mice, mitochondrial damage was more severe after TBI, indicating a potential association between APN/AdipoR1 signaling inactivation and mitochondrial damage. Mechanistically, neuron-specific knockout of SIRT3, the most important deacetylase in the mitochondria, reversed the neuroprotective effects of AdipoRon after TBI. Then, PRDX3, a critical antioxidant enzyme in the mitochondria, was identified as a vital downstream target of the APN/SIRT3 axis to alleviate oxidative injury after TBI. Finally, we revealed that APN/AdipoR1 signaling promotes SIRT3 transcription by activating the AMPK-PGC pathway. In conclusion, APN/AdipoR1 signaling plays a protective role in post-TBI oxidative damage by restoring the SIRT3-mediated mitochondrial homeostasis and antioxidant system.

线粒体功能障碍和氧化损伤导致神经功能缺损恶化和临床结果不佳，是 TBI 后继发性脑损伤的标志。脂联素 (APN) 除了对新陈代谢具有公认的调节作用外，还通过结合在大脑中普遍表达的 APN 受体来维持正常的大脑功能。目前，APN/APN受体（AdipoR）信号通路在TBI继发性损伤中的意义及具体机制尚未最终确定。在这项研究中，我们发现 APN 敲除会加重脑功能缺陷，增加脑水肿和病变体积，并加剧 TBI 后的氧化应激和细胞凋亡。在 APN 受体激动剂 (AdipoRon) 治疗后，这些影响显着减轻。而且，我们发现 AdipoR1 而非 AdipoR2 介导了 APN/AdipoR 信号传导对 TBI 后氧化应激和脑损伤的保护作用。在神经元特异性 AdipoR1 敲除小鼠中，TBI 后线粒体损伤更为严重，表明 APN/AdipoR1 信号通路失活与线粒体损伤之间存在潜在关联。从机制上讲，线粒体中最重要的脱乙酰酶 SIRT3 的神经元特异性敲除逆转了 AdipoRon 在 TBI 后的神经保护作用。然后，线粒体中的关键抗氧化酶 PRDX3 被确定为 APN/SIRT3 轴的重要下游靶标，以减轻 TBI 后的氧化损伤。最后，我们发现 APN/AdipoR1 信号通过激活 AMPK-PGC 通路促进 SIRT3 转录。综上所述，