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

## TL;DR

The paper shows that c-MAF and Slc40a1 protect against brain damage in sepsis by preventing a type of cell death called ferroptosis.

## Contribution

The study identifies a new regulatory axis (c-MAF/Slc40a1) that transcriptionally represses ferroptosis in sepsis-associated encephalopathy.

## Key findings

- c-MAF transcriptionally activates Slc40a1 to suppress ferroptosis in hippocampal neurons during sepsis.
- Neuron-specific knockdown of c-MAF or Slc40a1 worsens cognitive deficits and oxidative stress in sepsis.
- Overexpression of c-MAF or Slc40a1 reduces ferroptosis and improves survival and cognition in septic mice.

## Abstract

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.

c‐MAF and its downstream target Slc40a1 were identified as key regulators of ferroptosis in septic mouse hippocampi. Neuron‐specific knockdown of either gene aggravated CLP‐induced cognitive deficits and ferroptosis, whereas their overexpression exerted protective effects. c‐MAF directly activates Slc40a1 transcription, indicating the c‐MAF/Slc40a1 axis as a potential therapeutic target for SAE.