Gut microbiota-regulated cell death: a review on pyroptosis, ferroptosis, and related mechanisms

The intestinal microbiota has emerged as a crucial regulator of host physiological functions, significantly influencing various forms of regulated cell death (RCD). Among these, pyroptosis and ferroptosis play pivotal roles in immune regulation, metabolic homeostasis, and disease progression. The gut microbiota modulates these cell-death pathways through microbial metabolites, inflammatory signaling, oxidative stress, and immune-cell polarization, thereby affecting intestinal disorders, metabolic diseases, cardiovascular diseases, and neurodegenerative diseases. However, current evidence remains fragmented across individual cell-death pathways, and direct microbiota-mediated regulation is often not clearly distinguished from indirect associations arising from barrier dysfunction, inflammation, or metabolic remodeling. This review critically synthesizes the regulatory networks linking the gut microbiota to pyroptosis, ferroptosis, and related cell-death mechanisms. Throughout, we use RCD as the umbrella term for genetically encoded death programs and reserve programmed cell death (PCD) for its physiological, developmental subset, and we grade the supporting evidence at four levels: direct microbial regulation of the death machinery, experimentally demonstrated microbiota-dependent regulation, indirect effects mediated by barrier dysfunction or inflammation, and purely observational association. By integrating recent findings, we discuss the potential and limitations of therapeutic strategies targeting microbiota-regulated cell death. This synthesis provides a framework for defining current evidence gaps and guiding future mechanistic and translational studies.