Random‐pattern skin flaps are widely applied to rebuild and restore soft‐tissue damage in reconstructive surgery; however, ischemia and subsequent ischemia‐reperfusion injury lead to flap necrosis and are major complications. Exenatide, a glucagon‐like peptide‐1 analog, exerts therapeutic benefits for diabetic wounds, cardiac injury, and nonalcoholic fatty liver disease. Furthermore, Exenatide is a known activator of autophagy, which is a complex process of subcellular degradation that may enhance the viability of random skin flaps. In this study, we explored whether exenatide can improve skin flap survival. Our results showed that exenatide augments autophagy, increases flap viability, enhances angiogenesis, reduces oxidative stress, and alleviates pyroptosis. Coadministration of exenatide with 3‐methyladenine and chloroquine, potent inhibitors of autophagy, reversed the beneficial effects, suggesting that the therapeutic benefits of exenatide for skin flaps are due largely to autophagy activation. Mechanistically, we identified that exenatide enhanced activation and nuclear translocation of TFE3, which leads to autophagy activation. Furthermore, we found that exenatide activates the AMPK–SKP2–CARM1 and AMPK–mTOR signaling pathways, which likely lead to exenatide's effects on activating TFE3. Overall, our findings suggest that exenatide may be a potent therapy to prevent flap necrosis, and we also reveal novel mechanistic insight into exenatide's effect on flap survival.

中文翻译：

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艾塞那肽通过 TFE3 介导的自噬增强提高随机模式皮瓣的存活率


随机图案皮瓣广泛应用于重建手术中软组织损伤的重建和恢复；然而，缺血和随后的缺血再灌注损伤会导致皮瓣坏死，是主要并发症。艾塞那肽是一种胰高血糖素样肽-1类似物，对糖尿病伤口、心脏损伤和非酒精性脂肪肝具有治疗作用。此外，艾塞那肽是一种已知的自噬激活剂，自噬是一个复杂的亚细胞降解过程，可以增强随机皮瓣的活力。在这项研究中，我们探讨了艾塞那肽是否可以提高皮瓣的存活率。我们的结果表明，艾塞那肽增强自噬，增加皮瓣活力，增强血管生成，减少氧化应激，并减轻细胞焦亡。艾塞那肽与 3-甲基腺嘌呤和氯喹（自噬的有效抑制剂）共同给药，逆转了有益效果，表明艾塞那肽对皮瓣的治疗效果很大程度上归因于自噬激活。从机制上讲，我们发现艾塞那肽增强了 TFE3 的激活和核转位，从而导致自噬激活。此外，我们发现艾塞那肽激活 AMPK-SKP2-CARM1 和 AMPK-mTOR 信号通路，这可能导致艾塞那肽激活 TFE3 的作用。总的来说，我们的研究结果表明艾塞那肽可能是预防皮瓣坏死的有效疗法，并且我们还揭示了艾塞那肽对皮瓣存活影响的新机制。