Epigenetic Regulation of Pyroptosis in Kidney Disease: From Molecular Mechanisms to Therapeutic Potential

Abstract: Kidney disease is a significant global health burden, driving substantial mortality and years of life lost. As a pro-inflammatory form of programmed cell death (PCD), pyroptosis is characterized by the rupture of the plasma membrane, cell lysis, and the release of intracellular contents. Emerging evidence has implicated pyroptosis as an important contributor to kidney disease pathogenesis, showing that it involves in structural damage and functional impairment in renal cells. Pyroptosis is regulated by genetically encoded intracellular mechanisms, with epigenetic modifications representing a prevalent and critical regulatory modality. Epigenetic regulation involves multiple regulatory layers, including DNA methylation, histone modifications, RNA modifications, and non-coding RNA-mediated regulation. This review explores how multiple epigenetic regulatory mechanisms collectively modulate pyroptosis and its crosstalk with other forms of PCD, highlighting their cell type-specific and context-dependent effects in kidney disease. Preclinical evidence indicates that these regulatory mechanisms modulate pyroptosis in renal tubular epithelial cells, podocytes, glomerular mesangial cells, macrophages, and renal cancer cells. This regulation may influence inflammatory responses, renal fibrosis, and tumor progression, potentially exerting renoprotective and antitumor effects. Building on this, we summarize emerging therapeutic strategies, including epigenetic-targeting drugs, Traditional Chinese Medicine interventions, and exosome-based therapies. These strategies aim to suppress excessive pyroptosis in non-malignant kidney diseases or induce tumor-cell pyroptosis in renal cancer. Future clinical trials are needed to validate these findings and facilitate their clinical translation. Keywords: kidney disease, epigenetics, pyroptosis, therapeutic implication