Regulated Cell Death in Reproductive Biology: Mechanisms and Therapeutic Opportunities
6 affiliations
- 1Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
- 2Department of Nursing, School of Health Sciences, University of Ioannina, 4th Kilometer National Highway Str. Ioannina-Athens, 45500 Ioannina, Greece
- 3University General Hospital of Patras, 26504 Rio, Greece
- 4Department of Reproductive Medicine and Surgery, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK
- 5Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
- 6Department of Obstetrics and Gynaecology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece
Abstract
Regulated cell death (RCD) has emerged as a fundamental determinant of cellular homeostasis and tissue remodeling, extending far beyond the classical concept of apoptosis. The identification of emerging RCD pathways, including ferroptosis, pyroptosis, necroptosis, cuproptosis, PANoptosis, and autophagy-dependent cell death, has expanded our understanding of reproductive physiology and disease. RCD mechanisms contribute to reproductive homeostasis and have been increasingly implicated in gametogenesis, folliculogenesis, embryonic development, implantation, placentation, and reproductive aging, while their dysregulation has been associated with infertility, recurrent implantation failure, recurrent pregnancy loss, pregnancy complications, endometriosis, polycystic ovary syndrome (PCOS), gynecological malignancies, and male reproductive disorders. This review provides a comprehensive overview of the molecular mechanisms governing RCD across reproductive physiology and disease, emphasizing the complex interplay between oxidative stress (OS), mitochondrial dysfunction, inflammation, immune regulation, metabolic reprogramming, and genetic and epigenetic networks. Particular attention is given to the contribution of emerging cell death pathways to reproductive disorders and their interactions with environmental and lifestyle factors, including endocrine-disrupting chemicals. In addition, current evidence regarding RCD-associated biomarkers, multi-omics approaches, and therapeutic strategies targeting specific cell death pathways is critically evaluated, with particular emphasis on distinguishing associative molecular signatures from functional evidence of RCD execution. By integrating recent advances from basic, translational, and clinical research, this review highlights the context-dependent role of RCD in reproductive biology and disease and identifies current limitations and future opportunities for RCD-informed diagnostics, patient stratification, and targeted therapeutic interventions in reproductive medicine.
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BibTeX
@article{stavros2026regulated,
title = {{Regulated Cell Death in Reproductive Biology: Mechanisms and Therapeutic Opportunities}},
author = {Sofoklis Stavros and Efthalia Moustakli and Nikolaos Kathopoulis and Stefanos Dafopoulos and Dimos Sioutis and Athanasios Zikopoulos and Ismini Anagnostaki and Anastasios Potiris and Konstantinos Dafopoulos and Peter Drakakis},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201837},
url = {https://www.mdpi.com/2073-4409/15/20/1837},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Regulated Cell Death in Reproductive Biology: Mechanisms and Therapeutic Opportunities
AU - Sofoklis Stavros
AU - Efthalia Moustakli
AU - Nikolaos Kathopoulis
AU - Stefanos Dafopoulos
AU - Dimos Sioutis
AU - Athanasios Zikopoulos
AU - Ismini Anagnostaki
AU - Anastasios Potiris
AU - Konstantinos Dafopoulos
AU - Peter Drakakis
PY - 2026
DA - 2026/10/10
JO - Cells
DO - 10.3390/cells15201837
UR - https://www.mdpi.com/2073-4409/15/20/1837
AB - Regulated cell death (RCD) has emerged as a fundamental determinant of cellular homeostasis and tissue remodeling, extending far beyond the classical concept of apoptosis. The identification of emerging RCD pathways, including ferroptosis, pyroptosis, necroptosis, cuproptosis, PANoptosis, and autophagy-dependent cell death, has expanded our understanding of reproductive physiology and disease. RCD mechanisms contribute to reproductive homeostasis and have been increasingly implicated in gametogenesis, folliculogenesis, embryonic development, implantation, placentation, and reproductive aging, while their dysregulation has been associated with infertility, recurrent implantation failure, recurrent pregnancy loss, pregnancy complications, endometriosis, polycystic ovary syndrome (PCOS), gynecological malignancies, and male reproductive disorders. This review provides a comprehensive overview of the molecular mechanisms governing RCD across reproductive physiology and disease, emphasizing the complex interplay between oxidative stress (OS), mitochondrial dysfunction, inflammation, immune regulation, metabolic reprogramming, and genetic and epigenetic networks. Particular attention is given to the contribution of emerging cell death pathways to reproductive disorders and their interactions with environmental and lifestyle factors, including endocrine-disrupting chemicals. In addition, current evidence regarding RCD-associated biomarkers, multi-omics approaches, and therapeutic strategies targeting specific cell death pathways is critically evaluated, with particular emphasis on distinguishing associative molecular signatures from functional evidence of RCD execution. By integrating recent advances from basic, translational, and clinical research, this review highlights the context-dependent role of RCD in reproductive biology and disease and identifies current limitations and future opportunities for RCD-informed diagnostics, patient stratification, and targeted therapeutic interventions in reproductive medicine.
SN - 2073-4409
ER -