Ion channel Piezo1 induces ferroptosis of trabecular meshwork cells: a novel observation in the pathogenesis in primary open angle glaucoma

This study aims to elucidate the role of Piezo1, a mechanosensitive molecule, in trabecular meshwork cells (TMCs) in the context of primary open angle glaucoma (POAG), a leading cause of irreversible visual impairment. Dysfunction of the trabecular meshwork (TM) is a key factor in the elevated intraocular pressure (IOP) observed in POAG, yet the specific mechanisms leading to TM dysfunction are not fully understood. We performed cell stretching on human trabecular meshwork cells (HTMCs) and pharmacologically activated HTMCs with Yoda1 to study the role of Piezo1 in HTMCs. We focused on assessing cell viability, mitochondrial changes, lipid peroxidation, and the expression of ferroptosis-related targets such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). Cell stretching induces ferroptosis in HTMCs, and this phenomenon is reversed by Piezo1 knockdown. In addition, pharmacological activation of Piezo1 also leads to ferroptosis in HTMCs. Furthermore, inhibiting the JNK/p38 signaling pathway was found to mitigate the ferroptotic response induced by Yoda1, thereby confirming that Piezo1 induces ferroptosis in TMCs through this pathway. Notably, our experiments suggest that Yoda1 may trigger ferroptosis in the TM of mouse eyes. Our findings demonstrate that the Piezo1 pathway is a crucial mediator of ferroptosis in TMCs, providing new insights into the pathogenic mechanisms of glaucoma, particularly POAG. This study highlights the potential of targeting the Piezo1 pathway as a therapeutic approach for mitigating TM dysfunction and managing POAG.<b>NEW & NOTEWORTHY</b> This study is the first to show that cell stretching induces ferroptosis in trabecular meshwork cells (TMCs), dependent on Piezo1 activation. Targeting the Piezo1 pathway offers new therapeutic potential for mitigating trabecular meshwork dysfunction and managing primary open angle glaucoma (POAG). The study also reveals Piezo1 induces ferroptosis via the JNK/p38 signaling pathway.