Modulating Programmed Cell Death: Novel Targets and Novel Molecules

Programmed cell death (PCD) stands at the forefront of innovation in experimental pharmacology and drug discovery, providing fundamental insights into tissue homeostasis, development, and the mechanisms underlying diverse disease states. Since foundational studies in the mid-20th century, the field has grown far beyond its original starting point on apoptosis, expanding to more pathways such as necrosis/necroptosis, ferroptosis, parthanatos, and pyroptosis, among others. Each of these regulated cell death mechanisms is characterized by unique biochemical signatures and regulatory checkpoints that can serve as pharmacologically tractable targets. Recent research has revealed intricate crosstalk between these pathways and highlighted the importance of cell- and tissue-specific contexts in dictating cell fate outcomes. Despite this progress, major gaps remain—most notably, the identification and validation of novel druggable targets, a detailed understanding of pathway compensation and resistance mechanisms, and the selection of robust biomarkers for monitoring therapeutic intervention in both preclinical and clinical settings.

The clinical relevance of PCD modulation is underscored across a spectrum of diseases. One of the hallmarks of cancer is evasion of apoptosis, for example. While in neurodegenerative conditions and infectious diseases, inappropriate activation or suppression of cell death can drive pathology. The pharmacological manipulation of these pathways—through inhibition, activation, or pathway rewiring—has the potential to restore cellular balance, eliminate harmful cell populations, or protect healthy tissue. However, the translation of promising PCD-targeting agents from bench to bedside is complex. It requires careful integration of target potency and selectivity data, pharmacokinetic and pharmacodynamic (PK/PD) profiling, mechanistic studies to interpret drug action and anticipate resistance, and the identification of clinically meaningful biomarkers to guide patient selection and measure therapeutic response. The field stands to benefit greatly from a more systematic integration of molecular discovery, pharmacological validation, and translational science.

This Research Topic aims to accelerate progress by assembling cutting-edge research that furthers our understanding of the mechanisms governing programmed cell death and their exploitation for therapeutic gain. We seek contributions that span from early-stage target discovery and molecular profiling to advanced pharmacological evaluation, including in vitro and in vivo modeling, and translational studies bridging preclinical findings with early-phase clinical research. Our objective is to foster multidisciplinary dialogue and illuminate emerging challenges and opportunities—whether in the form of target validation, new therapeutic modalities, development and optimization of biomarkers, or strategies to mitigate resistance and toxicity. Ultimately, we envision a Research Topic that supports innovation across experimental pharmacology and drug discovery, catalyzing next-generation interventions for diseases rooted in aberrant cell death.

The scope of this Research Topic includes research and review articles addressing the modulation and pharmacology of the distinct programmed cell death pathways across both physiological and disease contexts. Submissions may focus on original experimental research, mechanistic studies, new assay development, modality innovation, brief reports, translational case studies, or comprehensive reviews. To gather further insights in the regulation and therapeutic targeting of cell death, we welcome articles addressing, but not limited to, the following themes:

o Discovery and validation of targets within PCD pathways using genetic, chemical, and systems biology approaches

o Development of new therapeutic modalities (small molecules, biologics, degraders, RNA therapeutics, gene editing, advanced delivery)

o Description of potential new pathways of PCD and their intersection with already described pathways

o Quantitative pharmacology, including lead optimization, ADME/PK profiling, PK/PD modeling, and cross-species translation

o Mechanistic studies and resistance mapping, including analysis of pathway crosstalk and rationale for combination therapies

o Biomarker strategy encompassing target engagement, pharmacodynamic monitoring, advanced imaging, and patient stratification

o Preclinical efficacy and safety assessment, immune consequences, dose and scheduling optimization, and toxicity management

o Translational approaches spanning model selection, early clinical trial design, and case studies of PCD-targeting agents across disease areas such as cancer, autoimmune and inflammatory disorders, infectious diseases, neurodegeneration, and tissue regeneration

We welcome original and review articles, brief reports, methods papers, and translational studies that explicitly link molecular intervention with pharmacological outcome and clinical potential.

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

Keywords: Apoptosis, Necroptosis, Ferroptosis, Pyroptosis, Target Validation, Biomarker Strategy, Translational Pharmacology

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.