c-MAF Transcriptionally Activates Slc40a1 to Repress Ferroptosis in Sepsis-Associated Encephalopathy

Ferroptosis, an iron-dependent programmed cell death driven by lipid peroxidation, has emerged as a potential contributor to sepsis-associated encephalopathy (SAE). However, the relationship between ferroptosis and cognitive deficits following sepsis needs to be further elucidated.

Transcriptome sequencing was employed to identify solute carrier family 40 member 1 (Slc40a1) as a candidate ferroptosis-related gene in the hippocampus of septic mice. The SAE mouse model was established via cecal ligation and perforation (CLP) after treatment with recombinant adeno-associated virus 9 (AAV9)-CaMKII to knock down or overexpress musculoaponeurotic fibrosarcoma (c-Maf) or Slc40a1. We assessed cognitive performance, Nissl staining, and ferroptosis-associated parameters. Dual-luciferase reporter gene assays and chromatin immunoprecipitation assays were performed to illuminate the mechanism by which c-MAF transcriptionally activates Slc40a1.

Hippocampal neurons of mice subjected to CLP showed downregulation of Slc40a1. Neuron-specific knockdown of Slc40a1 or c-Maf deteriorated sepsis-induced cognitive impairment, oxidative stress, and ferroptosis. Conversely, overexpression of Slc40a1 or c-Maf attenuated acute mortality and cognitive impairment following CLP, hampered lipid peroxidation and iron deposition, and enhanced antioxidant capacity. Moreover, Slc40a1 silencing neutralized the anti-ferroptotic property of c-Maf in SAE. Mechanistically, c-MAF was found to directly bind to the Slc40a1 promoter and facilitate its transcription.

Our findings suggest that c-MAF/Slc40a1 may represent a promising prevention target for SAE.