Sleep restriction triggers clock rhythmic ferroptosis leading to flap necrosis, and melatonin-preconditioned MSC-derived exosomes delivering USP4 stabilise ARNTL to inhibit this process and enhance flap survival.
Sleep restriction was identified as an independent risk factor for flap necrosis in a retrospective clinical analysis.
Sleep restriction increases ferroptosis levels, disrupts the circadian rhythm of ferroptosis, and exacerbates flap damage in both human and murine models.
Melatonin-preconditioned bone marrow mesenchymal stromal cell-derived exosomes (MEXOs) enhanced therapeutic efficacy of flap repair by mitigating clock rhythmic ferroptosis.
Melatonin increased m6A modification to stabilise and enhance the translation of USP4 mRNA within MEXOs.
USP4 delivered by MEXOs directly interacted with and deubiquitinated ARNTL, stabilising its protein levels and suppressing ferroptosis in flap tissue.
Sleep restriction leads to impaired skin barrier function as a consequence of clock rhythmic ferroptosis.
The USP4-ARNTL axis was proposed as a novel therapeutic target for SR-induced flap necrosis with translational potential for clinical reconstructive surgery.
This research suggests that poor sleep before or after skin flap surgery — a procedure used in reconstructive surgery to cover wounds or repair tissue — significantly increases the risk of flap failure and tissue death. The researchers studied 344 patients and found that sleep restriction was a meaningful risk factor for flap necrosis. They then uncovered the biological reason: poor sleep disrupts the body's internal clock in a way that triggers a specific type of cell death called ferroptosis, and this cell death follows a rhythmic, clock-driven pattern that damages the skin's protective barrier and causes flap tissue to die. To address this problem, the researchers developed an engineered treatment using tiny particles called exosomes derived from bone marrow stem cells that had been pre-treated with melatonin (a hormone involved in sleep regulation). This melatonin preconditioning caused the exosomes to become enriched with a protective protein called USP4. When these melatonin-engineered exosomes were delivered to flap tissue, the USP4 they carried stabilised another protein called ARNTL — a master regulator of the body's circadian clock — by preventing its breakdown. Stabilising ARNTL suppressed the harmful rhythmic ferroptosis and improved flap survival. This research suggests that sleep quality is a clinically relevant but often overlooked factor in surgical outcomes for reconstructive procedures. It also proposes a novel biological strategy — using engineered exosomes to restore circadian clock function and block a specific form of cell death — that could potentially be developed into a therapeutic approach for patients undergoing flap surgery, particularly those who experience sleep disruption around the time of their procedure.
Jiang X, Wang Y, Zhang X, Deng H, Fang L, Tafadzwa C, et al.. (2026). Melatonin-engineered MSCs-exosomes deliver USP4 to stabilise ARNTL and inhibit clock rhythmic ferroptosis for enhanced flap survival.. Clinical and translational medicine. https://doi.org/10.1002/ctm2.70565