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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