From Proteostasis Collapse to Endothelial Failure: Mechanistic Pathways Linking Heat Stress, Regulated Cell Death, and Coagulopathy
7 affiliations
- 1Department of Forensic Medicine, Faculty of Medicine, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina
- 2Department of Chemistry, Faculty of Science, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina
- 3Department of Pathology, Faculty of Medicine, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina
- 4Department of Medical, Surgical and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95121 Catania, Italy
- 5Faculty of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy
- 6Department of Internal Medicine and Cardiology, Clinic for Heart, Blood Vessel and Rheumatic Diseases, Sarajevo University Clinical Centre, 71000 Sarajevo, Bosnia and Herzegovina
- 7Department of Psychology and Health Sciences, Faculty of Human Sciences, Education, and Sports, Pegaso University, 80143 Naples, Italy
Abstract
This review proposes an integrative mechanistic model that brings together apoptosis, pyroptosis, ferroptosis, necroptosis, and necrosis within the broader context of heat-induced proteostasis disruption. Rather than depicting a strictly sequential or fully validated causal pathway, the model provides a conceptual framework through which interactions among cellular stress responses, endothelial dysfunction, heatstroke-induced coagulopathy (HIC), and multiple organ dysfunction syndrome (MODS) may be understood. Under extreme heat stress, widespread protein unfolding and chaperone saturation activate the unfolded protein response, disrupt endoplasmic (ER) calcium homeostasis, and couple through Ca2+-mediated injury to mitochondrial dysfunction and oxidative stress. These processes are reciprocally amplifying: reactive oxygen species (ROS) from failing mitochondria deepen proteostatic damage and potentiate necroptotic and ferroptotic signaling, while inflammation-driven immune activation further increases ROS production, closing a self-reinforcing cycle. The resulting engagement of multiple RCD pathways, apoptosis, pyroptosis, ferroptosis, and necroptosis, each with qualitatively distinct DAMP signatures, promotes inflammasome activation and a cytokine storm that destabilizes the endothelial glycocalyx, impairs barrier integrity, and triggers a pro-coagulant shift underlying HIC. We further examine biomarker candidates reflecting these mechanisms, evaluate emerging therapeutic strategies, ranging from HSP modulation and antioxidant therapy to endothelial-protective agents, mitophagy regulators, and nanomedicine, and outline the future role of multi-omics, machine learning, and regenerative approaches. By bringing together molecular, cellular, vascular, and systemic processes into a single cohesive model, this review proposes a conceptual foundation to guide diagnostic refinement, therapeutic innovation, and forensic interpretation in severe heat-related injury.
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BibTeX
@article{dervisevic2026from,
title = {{From Proteostasis Collapse to Endothelial Failure: Mechanistic Pathways Linking Heat Stress, Regulated Cell Death, and Coagulopathy}},
author = {Emina Dervišević and Temima Ajanović and Nina Čamdžić and Monica Salerno and Cristoforo Pomara and Massimiliano Esposito and Mario Chisari and Amina Zorlak and Nejra Selak and Enisa Hodžić and Francesco Sessa},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219804},
url = {https://www.mdpi.com/1422-0067/27/21/9804},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From Proteostasis Collapse to Endothelial Failure: Mechanistic Pathways Linking Heat Stress, Regulated Cell Death, and Coagulopathy
AU - Emina Dervišević
AU - Temima Ajanović
AU - Nina Čamdžić
AU - Monica Salerno
AU - Cristoforo Pomara
AU - Massimiliano Esposito
AU - Mario Chisari
AU - Amina Zorlak
AU - Nejra Selak
AU - Enisa Hodžić
AU - Francesco Sessa
PY - 2026
DA - 2026/10/31
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219804
UR - https://www.mdpi.com/1422-0067/27/21/9804
AB - This review proposes an integrative mechanistic model that brings together apoptosis, pyroptosis, ferroptosis, necroptosis, and necrosis within the broader context of heat-induced proteostasis disruption. Rather than depicting a strictly sequential or fully validated causal pathway, the model provides a conceptual framework through which interactions among cellular stress responses, endothelial dysfunction, heatstroke-induced coagulopathy (HIC), and multiple organ dysfunction syndrome (MODS) may be understood. Under extreme heat stress, widespread protein unfolding and chaperone saturation activate the unfolded protein response, disrupt endoplasmic (ER) calcium homeostasis, and couple through Ca2+-mediated injury to mitochondrial dysfunction and oxidative stress. These processes are reciprocally amplifying: reactive oxygen species (ROS) from failing mitochondria deepen proteostatic damage and potentiate necroptotic and ferroptotic signaling, while inflammation-driven immune activation further increases ROS production, closing a self-reinforcing cycle. The resulting engagement of multiple RCD pathways, apoptosis, pyroptosis, ferroptosis, and necroptosis, each with qualitatively distinct DAMP signatures, promotes inflammasome activation and a cytokine storm that destabilizes the endothelial glycocalyx, impairs barrier integrity, and triggers a pro-coagulant shift underlying HIC. We further examine biomarker candidates reflecting these mechanisms, evaluate emerging therapeutic strategies, ranging from HSP modulation and antioxidant therapy to endothelial-protective agents, mitophagy regulators, and nanomedicine, and outline the future role of multi-omics, machine learning, and regenerative approaches. By bringing together molecular, cellular, vascular, and systemic processes into a single cohesive model, this review proposes a conceptual foundation to guide diagnostic refinement, therapeutic innovation, and forensic interpretation in severe heat-related injury.
SN - 1422-0067
ER -