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

This is the authors' abstract. We don't add key points for this paper.

• Serum APN levels are associated with the outcomes of TBI. • Neurons in AdipoR1 CKO mice exhibit increased ferroptosis susceptibility post-TBI. • AdipoR1 activation reduces neuronal ferroptosis susceptibility by inhibiting PUFAs biosynthesis via regulating ACC1. 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 (AdipoR1 CKO ) 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 the ferroptosis sensitivity 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.