Nigericin induced paraptosis-like cell death instead of pyroptosis in corneal keratocytes

Corneal wound healing involves complex cellular processes, including keratocyte cell death, which plays a pivotal role in initiating tissue repair. Recent studies suggest that pyroptosis, characterized by the release of pro-inflammatory factors, occurs during tissue repair which may also contribute to the inflammatory phase of corneal wound healing. In this study, we investigated the nature of cell death in human keratocytes treated with nigericin, a known pyroptosis inducer. Surprisingly, nigericin triggered a unique form of non-inflammatory cell death marked by extensive vacuolation, resembling paraptosis. Proteomic analysis revealed that our human keratocytes lack key components of the canonical pyroptosis pathway, including NLRP3, ASC, and caspase-1, potentially explaining the absence of pyroptosis in these cells. This process was further confirmed by the absence of caspase-3 activation and lack of ER stress, alongside increased autophagic marker LC3-II accumulation. These findings suggest that nigericin triggers a paraptosis-like cell death in keratocytes, rather than pyroptosis, highlighting an alternative mechanism of cell death in corneal wound healing that warrants further exploration.