2. Academic Validation
  3. Adiponectin ameliorates traumatic brain injury-induced ferroptosis through AMPK- ACC1 signaling pathway

Adiponectin ameliorates traumatic brain injury-induced ferroptosis through AMPK- ACC1 signaling pathway

  • Brain Behav Immun. 2025 Feb 11:126:160-175. doi: 10.1016/j.bbi.2025.01.020.
Yufeng Ge 1,  Tinghao Wang 2,  Qing Hu 1,  Xun Wu 3,  Yaning Cai 3,  Wendong Xie 4,  Shenghao Zhang 1,  Bodong Wang 5,  Jin Wang 6,  Tian Feng 1,  Dayun Feng 3,  Shunnan Ge 3,  Hao Guo 7,  Yan Qu 8,  Haixiao Liu 9
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 2 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Neurosurgery, The 83rd Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
  • 3 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China; Shaanxi Clinical Research Center for Neurosurgical Diseases, Xi'an, Shaanxi, China.
  • 4 Department of Orthopedics, Gansu Provincial Hospital, Gansu University of Chinese Medicine, Lanzhou, Gansu, China.
  • 5 Department of Neurosurgery, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, China.
  • 6 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Neurosurgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
  • 7 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China; Shaanxi Clinical Research Center for Neurosurgical Diseases, Xi'an, Shaanxi, China. Electronic address: guohao0622@163.com.
  • 8 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China; Shaanxi Clinical Research Center for Neurosurgical Diseases, Xi'an, Shaanxi, China. Electronic address: yanqu0123@fmmu.edu.cn.
  • 9 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China; Shaanxi Clinical Research Center for Neurosurgical Diseases, Xi'an, Shaanxi, China; Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address: lhxiao@fmmu.edu.cn.
PMID: 39947491 DOI: 10.1016/j.bbi.2025.01.020
Abstract

Various forms of neuronal death contribute to neurological injury after traumatic brain injury (TBI), leading to irreversible neurological deficits. Among these, Ferroptosis is a form of regulated cell death characterized by the accumulation of iron-dependent lipid hydroperoxides and induced by the incorporation of polyunsaturated fatty acids (PUFAs) into cellular membranes. Adiponectin (APN), a cytokine secreted by adipocytes, have showed neuroprotective effects by binding to Adiponectin receptors (AdipoRs), which are widely expressed in the central nervous system. However, the role of APN-AdipoRs signaling in Ferroptosis after TBI remains unexplored. Our clinical analysis revealed a significant correlation between serum levels of APN and 6-month outcomes of TBI patients. Subsequent studies confirmed that TBI-induced Ferroptosis was more pronounced in APN knockout mice compared to wild-type mice, while additional APN receptor agonist (AdipoRon) treatment significantly mitigated TBI induced Ferroptosis. Furthermore, AdipoR1 knockdown significantly diminished the protective effects of AdipoRon against erastin-induced Ferroptosis in primary neurons. Correspondingly, in the neuron-specific AdipoR1 conditional knockout (AdipoR1CKO) mice, neurons were more susceptible to Ferroptosis after TBI, leading to increased brain edema and lesion volume, and exacerbated neurological deficits. Mechanically, activation of APN-AdipoR1 signaling promoted adenosine monophosphate activated protein kinase (AMPK) -mediated phosphorylation of acetyl-CoA carboxylase-1 (ACC1), thus suppressed the PUFAs biosynthesis, which determines theferroptosissensitivity of neurons. Taken together, these findings provided compelling evidence for the protective role of APN-AdipoR1 signaling against TBI-induced Ferroptosis by inhibiting AMPK-ACC1.

Keywords

AMPK; Acetyl-CoA carboxylase; Adiponectin; Ferroptosis; Neurological deficit; Traumatic brain injury.

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