Mechanical activation of PIEZO1 drives AP-1-dependent PTGS2/PGE2 signaling and corneal inflammation

Abnormal mechanical stimulation, such as eye rubbing, is a critical risk factor for corneal diseases, yet the molecular mechanisms linking mechanical stimulation to inflammation remain unclear. Here, we show that mechanical stretch directly activates the mechanosensitive ion channel PIEZO1 in human corneal fibroblasts, leading to CA²⁺ influx and activation of the AP-1 transcription factor. This signaling cascade drives robust induction of PTGS2 and secretion of its downstream effector PGE2, which in turn promotes corneal inflammation and impairs fibroblast repair functions. Using a mouse eye-rubbing model, we demonstrate that PIEZO1 inhibition with GsMTx4 significantly reduces corneal thickening, neutrophil infiltration, and inflammatory gene expression. These findings identify a PIEZO1-Ca²⁺-AP-1-PTGS2/PGE2 axis as a core mechanotransduction pathway driving corneal inflammation. Given the widespread expression of PIEZO1, our results provide mechanistic insight into how abnormal mechanical forces trigger inflammatory responses, highlighting a potential framework for understanding mechano-inflammation across tissues.