Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis

Pyroptosis, apoptosis, necroptosis, and ferroptosis, which are the most well-studied regulated cell death (RCD) pathways, contribute to the clearance of infected or potentially neoplastic cells, highlighting their importance in homeostasis, host defense against pathogens, cancer, and a wide range of other pathologies. Although these four RCD pathways employ distinct molecular and cellular processes, emerging genetic and biochemical studies have suggested remarkable flexibility and crosstalk among them. The crosstalk among pyroptosis, apoptosis and necroptosis pathways is more evident in cellular responses to infection, which has led to the conceptualization of PANoptosis. In this review, we provide a brief overview of the molecular mechanisms of pyroptosis, apoptosis, necroptosis, and ferroptosis and their importance in maintaining homeostasis. We discuss the intricate crosstalk among these RCD pathways and the current evidence supporting PANoptosis, focusing on infectious diseases and cancer. Understanding the fundamental processes of various cell death pathways is crucial to inform the development of new therapeutics against many diseases, including infection, sterile inflammation, and cancer. Cell death: Interactions between different pathways The different pathways that cause cell death, which are activated under different conditions, have complex relationships and sometimes act together to fight infection or cancer. All the pathways eliminate cells damaged by disease or mutation and are important for development and disease resistance, but can affect immune responses to infection or cause damage if dysregulated. Rajendra Karki at Seoul National University in South Korea and co-workers review recent evidence revealing links, including common molecules, between the pathways. Because cancer cells can become resistant to anti-cancer drugs or to the usual closely regulated cell death pathway, the ability to trigger a different type of cell death or to activate all pathways holds great promise for cancer treatment. Improving our understanding of cell death could help in treating multiple diseases, from infection to cancer.