Mathematical Modeling of Cell Death and Survival: Toward an Integrated Computational Framework for Multi-Decision...

Mathematical modeling is essential for understanding the complex regulatory pathways governing cell death and survival, including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, and immunogenic cell death (ICD)-a functional category comprising diverse morphological types capable of activating immune responses. The growing number of models describing individual signaling pathways poses the challenge of integrating them into a cohesive framework. This review aims to identify common components across existing ordinary differential equation models that could serve as key nodes to merge distinct signaling modalities. Proposed models highlight Bcl-2, Bax, Ca², and p53 as shared regulators linking autophagy and apoptosis. Necroptosis and apoptosis are interconnected via TNF signaling network and modulated by caspase-8, c-FLIP, and NFκB, with RIPK1 acting as a critical hub directing pathway choice. Pyroptosis and apoptosis are co-regulated by NFκB, tBid, and caspases, while ferroptosis is modeled exclusively as an independent process, separate from other forms of cell death. Furthermore, existing models indicate that ICD intersects with necroptosis during oncolytic virotherapy, with pyroptosis in SARS-CoV-2 infection, and with apoptosis in the context of chemotherapy. Although several models address crosstalk between pairs of cell fate decisions, creating comprehensive frameworks that encompass three or more death modes remains an open challenge.