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Melatonin improves random skin flap survival by suppressing ferroptosis via Nrf2/HO-1 signaling in preclinical models

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"Melatonin enhanced flap viability by suppressing ferroptosis through nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling."

Study Overview

Researchers from Wenzhou Medical University and affiliated institutions published a study in Burns & Trauma (DOI: 10.1093/burnst/tkag012) on 2 February 2026. The team reported that melatonin significantly enhanced flap viability by suppressing ferroptosis through the Nrf2/HO-1 signaling pathway.

Methods and Results

  • Animal model: Random skin flap models were created in mice. Melatonin was administered for seven consecutive days after surgery.
  • Improved outcomes: Compared with saline-treated controls, melatonin-treated flaps showed larger viable areas, stronger laser Doppler blood-flow signals, improved tissue structure, fewer dying cells, and higher expression of angiogenesis-related markers (CD31, E-cadherin, MMP9).
  • Cellular evidence: In vitro, human umbilical vein endothelial cells (HUVECs) were treated with tert-butyl hydroperoxide (TBHP) to recreate oxidative injury. Melatonin improved cell viability, proliferation, migration, and tube formation.
  • Mechanistic insights: Introduction of erastin (a ferroptosis inducer) showed that melatonin reduced reactive oxygen species (ROS), lipid peroxidation, iron accumulation, and mitochondrial damage, while strengthening antioxidant defenses. It increased expression of ferroptosis-protective genes (SLC7A11, GPX4) and corresponding proteins.
  • Primate confirmation: In macaques, oral melatonin treatment improved flap survival, reduced necrotic changes, promoted angiogenesis, and showed no obvious adverse effects in routine blood and biochemical analyses.

Conclusions

The authors concluded that melatonin interrupts a specific injury process in which iron accumulation and lipid peroxidation push ischemic flap tissue toward ferroptosis.

  • Cross-model evidence (cells, mice, macaques) supports a link between ferroptosis control, vascular recovery, and flap survival.
  • Clinical potential: Melatonin is already used as a dietary supplement with a favorable safety profile, which may facilitate clinical evaluation.
  • Further work needed: Researchers note that future studies must define optimal dosage, timing, delivery route, and long-term outcomes in patients.