# Apoptotic Bodies Derived from Fibroblast‐Like Cells in Subcutaneous Connective Tissue Inhibit Ferroptosis in Ischaemic Flaps via the miR‐339‐5p/KEAP1/Nrf2 Axis

## TL;DR

Apoptotic bodies from fibroblast-like cells in connective tissue help prevent cell death in ischaemic flaps by inhibiting ferroptosis through a specific molecular pathway.

## Contribution

The study identifies a novel therapeutic strategy using apoptotic bodies to promote ischaemic flap survival via the miR-339-5p/KEAP1/Nrf2 axis.

## Key findings

- Apoptotic bodies derived from fibroblast-like cells inhibit ferroptosis in ischaemic flaps.
- These apoptotic bodies promote macrophage M1-to-M2 polarization and reduce oxidative stress.
- The miR-339-5p/KEAP1/Nrf2 axis is central to the therapeutic effects observed in ischaemic flap survival.

## Abstract

Preventing and treating avascular necrosis at the distal end of the flaps are critical to surgery success, but current treatments are not ideal. A recent study shows that apoptotic bodies (ABs) generated near the site of apoptosis can be taken up and promote cell proliferation. The study reveals that ABs derived from fibroblast‐like cells in the subcutaneous connective tissue (FSCT cells) of skin flaps promoted ischaemic flap survival. It is also found that ABs inhibited cell death and oxidative stress and promoted M1‐to‐M2 polarization in macrophages. Transcriptome sequencing and protein level testing demonstrated that ABs promoted ischaemic flap survival in endothelial cells and macrophages by inhibiting ferroptosis via the KEAP1‐Nrf2 axis. Furthermore, microRNA (miR) sequencing data and in vitro and in vivo experiments demonstrated that ABs inhibited KEAP1 by delivering miR‐339‐5p to exert therapeutic effects. In conclusion, FSCT cell‐derived ABs inhibited ferroptosis, promoted the macrophage M1‐to‐M2 transition via the miR‐339‐5p/KEAP1/Nrf2 axis and promoted ischaemic flap survival. These results provide a potential therapeutic strategy to promote ischaemic flap survival by administering ABs.

Preventing and treating avascular necrosis at the distal end of the flap are critical to surgery success, but current treatments are not ideal. The present study reveals subcutaneous connective tissue cells‐derived ABs inhibited ferroptosis via the miR‐339‐5p/KEAP1/Nrf2 axis and promoted ischaemic flap survival. The finding provides a potential therapeutic strategy to promote ischaemic flap survival by administering ABs.