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

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.

Bismuth Sulfide Nanoflowers Facilitated miR339 Delivery to Overcome Stemness and Radioresistance through Ubiquitin-Specific Peptidase 8 in Esophageal Cancer

“…Recently, the miR339/KEAP1/ Nrf2 axis was found to promote the macrophage M1-to-M2 transition and ischemic flap survival. 28 Besides, miR339 inhibits ferroptosis by promoting autophagic degradation of FTH1 through targeting ATG7 in liver cancer cells. 29 However, whether miR339 acts as a radiosensitizer to facilitate therapeutic efficacy remains unclear.…”

“…miR339, as a tumor suppressor, is a promising therapeutic target for clinical treatment of various tumors. Recently, the miR339/KEAP1/Nrf2 axis was found to promote the macrophage M1-to-M2 transition and ischemic flap survival . Besides, miR339 inhibits ferroptosis by promoting autophagic degradation of FTH1 through targeting ATG7 in liver cancer cells .…”