Fisetin promotes ischemic flap survival by enhancing autophagy via inhibition of the PI3K/Akt/mTOR signaling pathway

Abstract

Background and purpose

Random flaps are extensively applied in reconstructive surgeries for wound coverage and tissue repair. However, distal flap ischemia and necrosis remain common postoperative complications, severely limiting their clinical utility. Among these, ischemic necrosis is the most critical challenge. Fisetin, a natural flavonoid with anti-inflammatory and autophagy-regulating properties, has shown potential in tissue protection. This study aimed to evaluate whether fisetin could reduce distal flap necrosis by enhancing autophagy and to elucidate the underlying mechanisms involved.

Experimental approach

The flaps’ viability was evaluated by analyzing the survival area and blood flow measurement with laser Doppler techniques, as well as histological analysis. The molecular expressions that were quantified included autophagy, oxidative stress, pyroptosis, and angiogenesis markers using Western blotting, immunohistochemistry, and immunofluorescence. Additionally, these methods assisted in the evaluation of activity in the PI3K-Akt-mTOR signaling pathway in mice models.

Key results

Our results demonstrated that fisetin improved the survival rate of ischemic flaps. These beneficial effects of fisetin were associated with enhanced autophagy, reduced oxidative stress and pyroptosis, and improved angiogenesis. Together, these mechanisms contributed to increased ischemic flap survival. Moreover, fisetin was found to enhance autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway, subsequently reducing oxidative stress and pyroptosis, and ultimately improving ischemic flap survival.

Conclusion

and Implications: Fisetin can improve the viability of ischemic flaps through the promotion of autophagy and reduction of pyroptosis, making it a potential candidate for clinical application.