Proteins and cellular crowding in the Regulation of Cell Death Pathways

Cell death signaling pathways represent a cornerstone of cellular biology, with proteins orchestrating the initiation, propagation, and execution phases of cellular demise through mechanisms such as apoptosis, necroptosis, ferroptosis, pyroptosis, and autophagy-related death. A persistent challenge in this area is the translation of results from simplified, dilute experimental systems to physiologically relevant, crowded intracellular environments - where macromolecular content can reach dramatic concentrations and strongly alter biophysical processes. Recent advancements reveal that such crowding not only influences protein folding, stability, and intermolecular interactions but also imparts a critical regulatory layer to the assembly of death-inducing complexes like apoptosomes, inflammasomes, and necrosomes. These observations highlight significant gaps in our mechanistic understanding, with ongoing debates focusing on the real impact of crowding in disease, stress response, and ageing. Despite major progress, a unified framework that connects molecular crowding to the complexity of cell death regulation remains elusive and urgently needed.This Research Topic aims to bridge this crucial gap by fostering an integrative exploration of the effects of cellular crowding on protein structure, dynamics, and functional interactions within cell death pathways. The main objective is to elucidate how crowding modulates key protein behaviors - ranging from folding and misfolding propensities to the kinetics and thresholds of signaling and supramolecular complex assembly - across apoptosis, necroptosis, ferroptosis, pyroptosis, and autophagy-related processes. Specific questions addressed may include: How does crowding affect the assembly and functionality of death-related protein complexes? What are the consequences of altered protein dynamics for signaling fidelity or cell fate decision-making? The research will promote approaches that incorporate crowding-aware models into both basic and disease-oriented studies, ultimately driving innovations in therapeutic targeting.This Research Topic is limited to studies that directly address protein function, dynamics, and interactions under conditions of macromolecular crowding in relation to cell death regulation. Experimental, computational, and theoretical works employing physio-mimetic systems or advanced modelling are especially relevant.We welcome contributions on topics including, but not limited to:Effects of macromolecular crowding on protein folding, misfolding, and conformational dynamics in cell death regulatorsCrowding-dependent modulation of protein–protein interaction networks in apoptosis, necroptosis, ferroptosis, and related pathwaysAssembly, stability, and kinetics of multi-protein death complexes (apoptosomes, inflammasomes, necrosomes) under crowded conditionsRegulation of signaling thresholds and pathway crosstalk in dense intracellular environmentsImplications for cell death in disease contexts such as cancer, neurodegeneration, stress, and ageingIntegration of crowding mimetics, biophysical methods, advanced live-cell imaging, and molecular simulations in cell death researchContributions may include Original Research articles, Reviews, Mini-Reviews, Perspectives, Methods papers, and Brief Research Reports. Approaches integrating biophysical techniques, crowding mimetics, advanced imaging, simulations, or disease-relevant models are particularly encouraged. Topic editors: PRASHANTA KUMAR PANDA, Asimul Islam, ZAHOOR AHMAD PARRAY Source: https://www.frontiersin.org/research-topics/77827/proteins-and-cellular-crowding-in-the-regulation-of-cell-death-pathways