The Cell Death–Physiology Interplay: Non-Lethal Functions and Physiological Regulation of Death Pathways

Programmed cell death pathways are traditionally studied as binary execution programs. However, emerging evidence highlights a dynamic, bidirectional relationship between cell death machinery and cellular physiology. Classical death proteins - including caspases, BCL-2 family members, and necroptotic or pyroptotic regulators - are increasingly recognized for their vital “moonlighting” signaling functions in development, tissue remodeling, differentiation, and homeostatic adaptation.

Crucially, this machinery does not operate in a vacuum. The decision of whether these pathways trigger cellular demise, promote survival, or orchestrate non-lethal signaling is actively shaped, constrained, and repurposed by the cell’s physiological state. Core cellular processes - including metabolic flux, proteostasis, organelle dynamics, and stress responses - serve as critical regulators of cell death sensitivity and execution.

By hosting this Topic within Non-Apoptotic Regulated Cell Death and cross-listing with Model Systems in Cell Death, we aim to capture this continuum between survival, adaptation, and execution across different model organisms and physiological contexts.

We welcome Original Research, Reviews, Mini Reviews, and Perspective articles covering, but not limited to:

• Non-lethal and sublethal signaling functions of canonical cell death proteins (e.g., caspases, BCL-2 family members) in development, tissue remodeling, and regeneration.

• Mechanistic links between metabolism (including lipid metabolism, mitochondrial bioenergetics, and redox balance) and the modulation of cell death sensitivity or signaling outcomes.

• The role of proteostasis, the ubiquitin-proteasome system, and autophagy in tuning cell death pathways and enabling adaptive cellular outcomes.

• Organelle-driven regulation of cell death pathways, focusing on lysosomes, the endoplasmic reticulum, and lipid droplets as signaling hubs.

• Emerging or atypical forms of regulated cell death (such as ferroptosis, pyroptosis, and lysosome-dependent cell death) arising from metabolic or physiological imbalances.

• In vivo and model organism studies revealing how the interplay between cell death machinery and physiological states operates in tissue and developmental contexts.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Policy and Practice Reviews
• Registered Report
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: Non-apoptotic regulated cell death, Moonlighting functions of caspases, BCL-2 family signaling, Non-lethal caspase activity, Cell death and metabolic regulation, Mitochondrial bioenergetics and cell death, Proteostasis and autophagy in cell death

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.