Inflammasome-imprinted stem cells: how NLRP3 signaling reprograms stem cell fate, function, and therapeutic efficacy

Abstract Stem cell–based therapies have emerged as promising strategies for the treatment of neurodegenerative disorders and ischemic injury; however, their clinical translation remains limited by poor survival, impaired integration, and inconsistent therapeutic outcomes. While extensive research has focused on the immunomodulatory properties of stem cells, the reciprocal impact of inflammatory signaling on stem cell fate and function remains largely under-explored. In this review, we explore the emerging concept of “inflammasome imprinting,” where persistent NLRP3 inflammasome activation may induce long-lasting alterations in cellular metabolism and function that could influence regenerative capacity. Specifically, we will consider how the signaling pathway of the NLRP3 inflammasome functions as a vital intracellular marker of stress in stem cells, integrating external inflammation pathways into mitochondrial dysfunction, oxidative stress, and changes in stem cell differentiation abilities. Specific emphasis is placed on the possibility of interaction between NLRP3 inflammasome activation, oxidative stress in mitochondria, and post-translational modifications of SOD2, despite a lack of understanding of the mechanisms involved. Apart from affecting the viability of stem cells, the redox imbalance may contribute to the establishment of a persistent inflammatory phenotype. We also discuss the complex relationship between inflammasome activation, autophagy, and epigenetic reprogramming in stem cells, and how these processes may influence stem-cell survival under pathological conditions such as ischemic stroke and Alzheimer’s disease. This review proposes a conceptual framework through which chronic inflammasome activation may influence stem-cell function via the inflammasome–mitochondria axis.