Melatonin improves skin flap survival by reducing ferroptosis

Random-pattern skin flaps are widely used to repair defects caused by trauma, burns, tumor removal, and other injuries because they can be designed without depending on a single named blood vessel. However, this flexibility also makes the distal part of the flap vulnerable to poor perfusion, ischemia-reperfusion injury, inflammation, and necrosis. Current surgical and pharmacological approaches still do not fully prevent flap failure, and the biological mechanisms behind distal tissue loss remain difficult to control. Based on these challenges, deeper investigation is needed into safe, mechanism-based interventions that can preserve microcirculation and reduce ischemic flap injury.

Researchers from Wenzhou Medical University and affiliated institutions, including Affiliated Cixi Hospital, Oujiang Laboratory, Cixi Biomedical Research Institute, and Hainan Medical University, published the study (DOI: 10.1093/burnst/tkag012) in Burns & Trauma on 2 February 2026, reporting that melatonin enhanced flap viability by suppressing ferroptosis through nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling.

The team first created random skin flap models in mice and administered melatonin for seven consecutive days after surgery. 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, including cluster of differentiation 31 (CD31), E-cadherin, and matrix metallopeptidase 9 (MMP9). To recreate oxidative injury in vitro, the researchers treated human umbilical vein endothelial cells (HUVECs) with tert-butyl hydroperoxide (TBHP). Melatonin improved cell viability, proliferation, migration, and tube formation, suggesting that it helped restore endothelial functions needed for vascular repair. The team then introduced erastin, a ferroptosis inducer, to test whether ferroptosis was driving flap injury. Melatonin reduced reactive oxygen species (ROS), lipid peroxidation, iron accumulation, and mitochondrial damage, while strengthening antioxidant defenses. It also increased the expression of ferroptosis-protective genes, including SLC7A11 and GPX4, as well as the corresponding proteins SLC7A11 and GPX4. 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.

The authors said the study suggests melatonin does more than generally reduce oxidative stress. It appears to interrupt a specific injury process in which iron accumulation and lipid peroxidation push ischemic flap tissue toward ferroptosis. They said the cross-model evidence—from cells to mice and macaques—strengthens the biological link between ferroptosis control, vascular recovery, and flap survival. This gives reconstructive surgery a clearer molecular target and places melatonin among candidate therapies worth further clinical evaluation.

These findings may have implications for plastic surgery, burn repair, trauma reconstruction, and other procedures that depend on reliable flap survival. A treatment that preserves blood flow while limiting ferroptosis could help reduce distal necrosis, improve healing quality, and lower the risk of secondary procedures. Notably, melatonin is already widely utilized as a dietary supplement for sleep regulation and has demonstrated a favorable safety profile across various clinical applications, including its use as an adjuvant in oncology, cardiovascular protection, and the mitigation of neurodegenerative conditions. Given its high biological safety and established market availability, melatonin may be more clinically approachable than many experimental compounds. Further work is still needed to define optimal dosage, timing, delivery route, and long-term outcomes in patients, but the study provides an important preclinical foundation for ferroptosis-targeted flap protection.