Acetyl-CoA carboxylase activation disrupts iron homeostasis to drive ferroptosis.

Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in de novo lipogenesis. Here, we show a unique function of ACC in disrupting cellular iron homeostasis to drive ferroptosis, an iron-dependent, lipid peroxidation-induced form of cell death. We observed neuronal lipid accumulation and elevated labile iron pool associated with ACC dephosphorylation in mouse models of obstructive sleep apnea (OSA), a highly prevalent neurodegenerative disorder. ACC gene (Acaca) knockout (KO) or inhibition of its enzymatic activity rescued cellular iron metabolism through restoring lysosomal integrity and function, suppressing neuronal ferroptosis. ACC inactivation-driven lysosomal iron homeostasis requires the NFE2L2/NRF2-TFEB axis. Empagliflozin mitigates cellular iron overload via the ACC-NRF2-TFEB-lysosome pathway to alleviate neuronal ferroptosis, cognitive impairment, and mood dysfunction in OSA mice. Furthermore, inhibiting neuronal ACC reduces microglial activation, characterized by elevated complement proteins and pro-inflammatory cytokines, while microglia-specific C1qa KO prevents neuronal injury in OSA mice. Our findings identify a unique coupling between iron homeostasis and lipogenic signaling, suggesting ACC as a potential therapeutic target for neuronal ferroptosis and the resultant microgliosis in neurodegenerative diseases.