Crosstalk mechanisms among gut microbiota, novel programmed cell death, and macrophage polarization

Several disease conditions are associated with the abnormal activation of pyroptosis, ferroptosis, necroptosis, cuproptosis, and disulfidptosis, as well as dysregulated macrophage polarization, which collectively serve as hallmarks of tissue damage and organ dysfunction. Importantly, these emerging forms of programmed cell death are closely linked to intestinal microbiota homeostasis. The gut microbiota constitutes a key ecosystem that regulates host metabolism, immunity, and overall physiological balance. When gut microbiota dysbiosis occurs, it promotes the production of harmful metabolites and activates inflammatory signaling pathways. This leads to metabolic disturbances and chronic inflammation, which in turn can induce pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and polarization of macrophages toward the M1 phenotype. Therefore, a deeper understanding of the dynamic regulation of the gut microbiota in these forms of cell death and macrophage polarization is essential for comprehending the progression of related diseases. In this review, we systematically summarize the impact of gut microbiota and its metabolite alterations on the regulation of these novel programmed cell death pathways and macrophage polarization, aiming to advance the understanding of related disease pathogenesis and provide a theoretical foundation for potential therapeutic strategies. • The gut microbiota plays multiple regulatory roles in host physiological functions and is often termed the "second genome" or the "forgotten organ." • Crosstalk between the gut microbiota and novel cellular dysfunction mechanisms contributes to a range of diseases. • Targeted intervention of gut microbial metabolites presents a therapeutic strategy for ameliorating pathogenic cell death and treating related diseases through crosstalk mechanisms.