Sphingosine Kinase 1 (SphK1) inhibition accelerates corneal epithelial wound healing by reducing TGF-β/Smad signaling

Abnormal corneal wound healing often leads to corneal opacity, a major cause of blindness, due to complex and poorly understood signaling interactions. Current therapeutic strategies are limited by this knowledge gap. Both sphingosine-1-phosphate (S1P) and transforming growth factor beta (TGFβ) signaling are implicated in tissue fibrosis. This study investigates their interplay in corneal wound healing and fibrosis development.

Researchers subjected Sphk1-/- mice and wildtype littermates to corneal injury by alkali burn. They measured wound healing progress and the expression/activation of TGFβ signaling intermediates and profibrotic proteins at different days post-injury (DPI). Additionally, wildtype (Sphk1+/+) mice received exogenous delivery of a small-molecule inhibitor of sphingosine kinase 1 (SphK1) to assess its impact on corneal wound healing after similar injury.

Reduction of S1P signaling in Sphk1-/- mice significantly induced the closure of the corneal epithelial layer at a faster rate than wildtype littermates following alkali burn.

Reduced activation of profibrotic proteins Smad2 and Smad3, along with reduced expression of Smad4, was observed in Sphk1-/- mice compared to wildtype littermates post-injury. Crucially, Sphk1-/- mice also showed higher expression of the antifibrotic protein Smad7. Furthermore, exogenous inhibition of S1P signaling via a small-molecule SphK1 inhibitor could accelerate corneal wound healing in similarly injured wildtype (Sphk1+/+) mice. These findings collectively indicate that S1P signaling positively influences TGFβ pathways, which in turn negatively affect corneal wound healing by delaying closure and promoting fibrotic development.