Death Receptors and Stress Signaling Pathways in Therapeutic Intervention

Death receptors — members of the tumor necrosis factor receptor (TNFR) superfamily, including Fas (CD95), TNFR1, DR4, and DR5 — are critical mediators of programmed cell death and inflammatory signaling. When activated by their cognate ligands or by cellular stress, these receptors converge with intracellular stress signaling networks — including the unfolded protein response (UPR), oxidative stress pathways, DNA damage response, and mitochondrial dysfunction — to determine cell fate between survival, apoptosis, necroptosis, and autophagy.

Dysregulation of death receptor signaling and stress-response cascades underpins a wide range of pathological conditions, including cancer, neurodegenerative diseases, cardiovascular disorders, and chronic inflammatory diseases. As such, these pathways have emerged as compelling targets for therapeutic intervention. TRAIL-based therapies, small-molecule sensitizers, kinase inhibitors, and combination strategies that exploit stress-induced vulnerabilities are among the most actively investigated approaches in experimental pharmacology and drug discovery.

This Research Topic invites original research articles, reviews, and perspectives that explore the pharmacological modulation of death receptor pathways and stress signaling networks in the context of disease. We welcome contributions addressing, but not limited to, the following themes:

Mechanistic studies of death receptor activation, signal transduction, and crosstalk with stress pathways

Drug discovery efforts targeting TRAIL receptors, Fas/FasL, TNFR1, and downstream effectors

The role of ER stress, oxidative stress, and the DNA damage response in sensitizing cells to death receptor-mediated apoptosis

Resistance mechanisms and strategies to overcome them in cancer and other diseases

Novel small molecules, biologics, and combination therapies exploiting death receptor and stress signaling vulnerabilities

Preclinical models and translational approaches bridging experimental findings to therapeutic applications

Article types and fees

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

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... 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
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Death Receptors, Apoptosis, TRAIL, Stress Signaling, Drug Discovery, Cancer Therapeutics, Caspase Activation

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.