Integrated Programs and Mechanistic Crosstalk in Regulated Cell Death

Regulated cell death represents a dynamic field at the intersection of molecular biology, biochemistry, and cell signaling. Over recent decades, our understanding of cell death has evolved from viewing pathways such as apoptosis or necroptosis as isolated modules, to realizing that cells traverse a complex web of interlinked programs with overlapping, sequential, or even simultaneous features. Emerging data highlight the increasingly blurred borders between cell death modalities, where cells may display mixed biochemical markers, partial phenotypic hallmarks, and anomalous signaling patterns that deviate from traditional dogma. This complex crosstalk raises unresolved questions: are we seeing sequential fate switching, genuine co-activation, or simply population-level heterogeneity and methodological artifacts? Despite key advances in revealing routing nodes, stress-specific triggers, and the flexibility of cellular demise, the field struggles with ambiguities regarding mechanistic causality, standards for crosstalk assignments, and robust interpretation of multi-modal phenotypes.

This Research Topic aims to dissect the underlying logic and molecular mechanisms that govern switching, commitment, and coexistence between regulated cell death programs. By fostering a debate-led and evidence-driven approach, we seek to clarify nodes of cross-regulation, decipher the biological relevance of “decision points,” and distinguish true mechanistic integration from correlated cell death signaling. Central objectives include systematically identifying the thresholds, checkpoints, and intracellular determinants that tip cells between alternative fates, as well as experimentally adjudicating between competing mechanistic models. Through synthesis of original research, perspectives that challenge prevailing hypotheses, and methodological advances, this initiative will stimulate constructive discourse, accelerate standardization in approaches, and chart a path toward consensus on some of the most persistent controversies in the field.

The scope of this Research Topic is focused on mechanistic studies and debates surrounding the integration, switching, and coexistence of regulated cell death pathways. Descriptive papers without precise mechanistic insight or studies limited to single-pathway outcomes fall outside this focus. To gather further insights into the molecular, cellular, and contextual dynamics of cell death crosstalk, we welcome articles addressing, but not limited to, the following themes:

1. Discriminating between cell death pathway switching, and true co-activation versus population- or time-dependent heterogeneity.

2. Investigation of commitment points, thresholds, and kinetic properties underlying irreversible cell fate decisions.

3. Identification and characterization of shared routing modules, including scaffolds, proteases, organelle hubs, and redox regulators.

4. Mechanistic studies on execution events: membrane permeabilization, rupture, and functional outcomes.

5. Disentangling death execution from parallel signaling, including inflammatory programs, DAMP release, and secondary necrosis.

6. Exploration of the effects of metabolic state, differentiation, stress responses, and microenvironment on cell death outcomes.

7. Comparative analysis and methodological advances for robustly distinguishing mixed or hybrid phenotypes.

Submissions are encouraged in the form of Original Research, Methods, Brief Research Reports, Perspectives, Opinions, Reviews/Mini Reviews, and Commentaries. Where applicable, authors should clearly state which mechanistic controversy/ambiguity their work addresses and include falsifiable predictions or debate relevance in a designated summary box.

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: cell death crosstalk, regulated cell death, cell death pathway switching, apoptosis and necroptosis, mixed cell death phenotypes, cell fate decision making, death pathway co-activation, molecular mechanisms of cell death, cell death signaling networks, cell death debate, crosstalk between regulated cell death pathways

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.