From Glycans to Mitochondria: Women Scientists Map the Frontiers of Cell Death Research

Cell stress responses occupy one of the most fascinating frontiers in modern biology, standing at the delicate interface between adaptation and demise. When cells confront environmental challenges, metabolic imbalance, or developmental cues, the outcome of stress signaling can determine whether they survive, transform into malignant states, or undergo programmed death. A new Research Topic published in Frontiers in Cell Death, introduced by an editorial from Rosa Bonaventura of the Institute for Biomedical Research and Innovation in Palermo and Chiara Gambardella of the Institute for the Study of Anthropogenic Impacts and Sustainability in the Marine Environment in Genoa, gathers five articles that illuminate this complexity. Together, the contributions offer fresh perspectives on cellular and molecular checkpoints, evolutionary models, and the implications of stress biology for human disease, and they do so under a banner that highlights the central role of women scientists in the field of cell death research.

The first of the collected reviews, titled Die Hard: Necroptosis and its Impact on Age-Dependent Neuroinflammatory Diseases, addresses a form of programmed non-apoptotic cell death known as necroptosis, which is increasingly recognized as a driver of neurodegeneration. Unlike classical apoptosis, necroptosis is a regulated, lytic form of death that dismantles cellular membranes and releases danger signals into the surrounding tissue, fueling inflammation. The authors trace necroptosis from its historical background to recent insights into the signaling and regulatory mechanisms that operate in several age-dependent neuroinflammatory diseases. They go beyond mechanism, examining the therapeutic inhibitors that have been developed to block the necroptotic cascade and the outcomes observed when these molecules are deployed, and they discuss in vitro methods for inducing necroptosis in controlled laboratory settings. This dual focus on fundamental signaling and practical methodology expands the knowledge base around a pathway with potential therapeutic benefits across a spectrum of neuroinflammatory conditions that become more prevalent with age.

A second review shifts attention from the manner of cell death to the molecular decorations that decide when death signals fire. Glycans on Death Receptors as Sweet Markers and Signaling Checkpoints provides an overview of current understanding of how glycosylation, the attachment of complex sugar chains, modulates cell signaling through death receptors. The activation of these receptors triggers the extrinsic death pathway, the route by which external signals instruct a cell to self-destruct. The glycans attached to death receptors display remarkable structural diversity, and understanding their involvement in signal transduction is crucial for deciphering what researchers call the glyco-code, the specific glycan signatures that encode biological information. Far from being passive ornaments, glycans act as functional modulators capable of shaping the activities of death receptors and the intracellular signaling they initiate. This view opens exciting avenues for future therapeutic strategies in which glycosylation itself could be targeted to fine-tune death receptor pathways, either dampening pathological cell loss or sharpening the elimination of unwanted cells.

Complementing this receptor-centered perspective, a third contribution revisits the organelle that sits at the heart of cellular life-and-death decisions. In Mitochondrial (dys)function: a double edge sword in cell stress response, the authors present mitochondria not merely as energy producers but as pivotal decision-makers in stress adaptation. The review focuses on mitochondrial communication and its relevance for cytoprotective strategies aimed at controlling the synthesis, degradation, and recycling of cellular components. Crucially, the authors propose the budding yeast Saccharomyces cerevisiae as a suitable model organism for gaining insights into retrograde response pathways and autophagic and mitophagic processes, the mechanisms by which cells remodel their metabolism to compensate for the loss of mitochondrial function and clear damaged organelles. Depending on the circumstances, these processes either promote metabolic remodeling that provides building blocks for amino acid and protein synthesis or remove impaired organelles that would otherwise poison the cell. The double-edged character of the title reflects the fact that the same mitochondrial dysfunction that threatens survival can, when properly managed, trigger adaptive programs that preserve life.

The theme of metabolic stress is expanded further in the fourth contribution, Exploring Sugar-Induced Cell Death in Yeast: Implications for Diabetes and Cancer Research, which uses yeast as a powerful model to dissect how an excess of sugar can trigger lethal signaling cascades. Sugar-induced cell death was first described in Saccharomyces cerevisiae in 1991, and the review summarizes the current understanding of this phenomenon, which has accumulated over more than three decades. What makes the topic newly urgent is the highlighted evidence that a similar process operates in mammalian cells, where it is known as high glucose induced cell death. This connection carries weighty implications for two of the most burdensome diseases of modern life. In diabetes, chronically elevated glucose contributes to tissue damage, and understanding how surplus sugar kills cells could clarify the mechanisms of diabetic complications. Conversely, cancer cells have evolved mechanisms to evade high glucose induced cell death, thriving in the sugar-rich environments of tumors, and dissecting those escape routes may reveal vulnerabilities that can be exploited therapeutically.

The fifth article in the collection widens the lens from single cells and model organisms to the stress responses of a whole developing animal. In The sea urchin embryo and the cell stress responses: new perspectives, the authors examine how the sea urchin embryo, a model used worldwide across many research fields, responds at the gene level to challenging conditions. They provide an updated account of the current knowledge of sea urchin embryo genes involved in the cellular stress response following exposure to different environmental conditions and pollutants. A selection of studies employing high-throughput screening approaches was taken into consideration, allowing the authors to survey broad swaths of stress-responsive gene expression rather than isolated markers. The perspective emerging from this work is the identification of panels of modulated genes that could be exploited as biomarkers of embryotoxicity, providing new approaches for monitoring and intervention strategies in environments affected by chemical contamination.

The sea urchin contribution carries particular resonance given the research profile of the editorial’s co-authors, whose institutions in Palermo and Genoa sit at the intersection of biomedical innovation and marine environmental science. By coupling developmental biology with ecotoxicology, the review points toward practical tools: standardized gene panels that environmental agencies could deploy to assess whether coastal waters or industrial discharges pose risks to embryonic development. Because sea urchin embryos develop externally and are exquisitely sensitive to water chemistry, they serve as living sensors whose stress gene expression patterns report on the health of their surroundings. In this way, fundamental curiosity about how embryos cope with stress translates directly into instruments for environmental protection, an example of how cell death research ripples outward into applied science.

Viewed side by side, the five articles reveal an unexpected coherence across scales and systems. From glycans to mitochondria, from yeast to humans through the sea urchin, and from cancer to neurodegeneration, the contributions converge on a central message: cellular fate under stress is determined by finely orchestrated networks, whose perturbation can lead to pathology but whose understanding holds the promise of innovative treatments and intervention strategies across many different fields. The necroptosis review links lytic death to brain inflammation; the glyco-code review shows how sugar chains gate the extrinsic death pathway; the mitochondrial and yeast studies expose the metabolic logic of survival decisions; and the sea urchin work demonstrates that the same stress-response architecture can serve as an environmental early-warning system. Each article fills in a different corner of the same map, and the map as a whole is drawn substantially by women scientists.

That final point is the explicit purpose of the Research Topic series in which this collection appears. By curating a special issue dedicated to women in cell death research, the editors draw attention to both the scientific breadth and the community of researchers behind the field’s progress. Cell death research itself has a history of redefining boundaries, from the recognition of apoptosis as programmed suicide, to the discovery of necroptosis as a regulated alternative, to the current appreciation of non-lethal stress responses as determinants of cellular destiny. The five articles gathered here, spanning neuroinflammatory disease, glycosylation, mitochondrial communication, sugar-induced death, and embryonic biomarkers, illustrate how a field once narrowly concerned with how cells die has matured into one that asks, more fundamentally, how cells decide. The editorial by Bonaventura and Gambardella frames this scientific arc as a collective achievement and invites readers to follow the work of the researchers, and the model systems, assembled within the topic.

For the broader scientific community, the message of this collection is one of convergence and opportunity. The therapeutic implications run in parallel tracks: inhibitors of necroptotic signaling hold promise for neuroinflammatory disease; glyco-code manipulation could retune death receptor pathways; mitophagy-targeting cytoprotective strategies may preserve failing tissues; and the vulnerabilities of cancer cells to high glucose induced death suggest metabolic approaches to oncology. Meanwhile, embryotoxicity biomarkers derived from sea urchin stress genes offer a concrete route to environmental monitoring. That such varied applications spring from a single Research Topic, introduced by an editorial celebrating women in the field, underscores how the study of stress and death has become one of biology’s most connective disciplines, linking clinical medicine, developmental biology, and ecology through the shared language of cellular decisions.

Subject of Research: Cell stress response and programmed cell death mechanisms across model systems, from necroptosis and glycosylated death receptors to mitochondrial dysfunction, sugar-induced cell death, and embryotoxicity biomarkers

Article Title: Editorial: Women in cell death research

Article References: Bonaventura, R., & Gambardella, C. (2025). Editorial: Women in cell death research. Frontiers in Cell Death, 4, Article 1704003. https://doi.org/10.3389/fceld.2025.1704003

Image Credits: AI Generated

DOI: 10.3389/fceld.2025.1704003

Keywords: cell death, necroptosis, death receptors, glyco-code, glycosylation, mitochondrial dysfunction, autophagy, mitophagy, sugar-induced cell death, yeast, sea urchin embryo, neuroinflammation