Abstract
Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na(+)) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na(+) transporters have been identified as a functional regulator of regeneration. However, the role of Na(+) in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na(+) ionophores that were employed to increase intracellular Na(+) content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na(+) decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na(+) ionophores replenish H(+) to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na(+), which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na(+) ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.