Zonula occludens-1 at the ischemic blood–brain barrier: mechanisms of disruption, functional significance, and experimental modulation
- 1Department of Neurology, Chest Hospital of Shenyang Pharmaceutical University, Liaoning Province, China
Abstract
Blood–brain barrier (BBB) disruption is a major component of ischemic brain injury, yet the contribution of zonula occludens-1 (ZO-1) is often inferred from changes in total protein abundance. Here we synthesize evidence showing that ZO-1 is instead a dynamically regulated junctional scaffold whose disruption encompasses mechanistically distinct states. Ischemia and reperfusion alter ZO-1 through caveolin-dependent internalization and endolysosomal degradation, phosphorylation and cytoskeletal redistribution, transcriptional and epigenetic regulation, and convergent oxidative, inflammatory, metabolic and multicellular signaling. These mechanisms can impair junctional continuity and paracellular barrier function without necessarily reducing total ZO-1. Conversely, BBB permeability can improve without proportional recovery of ZO-1 abundance, reflecting contributions from transcellular transport, the basal lamina and other neurovascular components. Numerous interventions preserve or restore ZO-1 alongside reduced leakage, edema or hemorrhagic transformation, but most act on upstream injury pathways and do not establish that ZO-1 is necessary for barrier rescue. We therefore propose that ZO-1 should be interpreted as a mechanistically informative readout of endothelial junctional integrity rather than a universal surrogate for BBB recovery or a validated therapeutic target. The available evidence remains predominantly preclinical, while limited clinical studies have evaluated circulating ZO-1 and other tight-junction proteins as biomarkers rather than directly assessing endothelial junctional ZO-1 in the ischemic brain. Translation will therefore require confirmation of ZO-1 molecular states and causal relevance in human BBB systems and patient-level studies, together with clinically relevant reperfusion, comorbidity, and treatment-window paradigms.
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BibTeX
@article{zhou2026zonula,
title = {{Zonula occludens-1 at the ischemic blood–brain barrier: mechanisms of disruption, functional significance, and experimental modulation}},
author = {Bosi Zhou and Zhihan Wang and Xuefeng Jing and Bing Xu and Xue Qin},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1967401},
url = {https://doi.org/10.3389/fcell.2026.1967401},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Zonula occludens-1 at the ischemic blood–brain barrier: mechanisms of disruption, functional significance, and experimental modulation
AU - Bosi Zhou
AU - Zhihan Wang
AU - Xuefeng Jing
AU - Bing Xu
AU - Xue Qin
PY - 2026
DA - 2026/10/21
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1967401
UR - https://doi.org/10.3389/fcell.2026.1967401
AB - Blood–brain barrier (BBB) disruption is a major component of ischemic brain injury, yet the contribution of zonula occludens-1 (ZO-1) is often inferred from changes in total protein abundance. Here we synthesize evidence showing that ZO-1 is instead a dynamically regulated junctional scaffold whose disruption encompasses mechanistically distinct states. Ischemia and reperfusion alter ZO-1 through caveolin-dependent internalization and endolysosomal degradation, phosphorylation and cytoskeletal redistribution, transcriptional and epigenetic regulation, and convergent oxidative, inflammatory, metabolic and multicellular signaling. These mechanisms can impair junctional continuity and paracellular barrier function without necessarily reducing total ZO-1. Conversely, BBB permeability can improve without proportional recovery of ZO-1 abundance, reflecting contributions from transcellular transport, the basal lamina and other neurovascular components. Numerous interventions preserve or restore ZO-1 alongside reduced leakage, edema or hemorrhagic transformation, but most act on upstream injury pathways and do not establish that ZO-1 is necessary for barrier rescue. We therefore propose that ZO-1 should be interpreted as a mechanistically informative readout of endothelial junctional integrity rather than a universal surrogate for BBB recovery or a validated therapeutic target. The available evidence remains predominantly preclinical, while limited clinical studies have evaluated circulating ZO-1 and other tight-junction proteins as biomarkers rather than directly assessing endothelial junctional ZO-1 in the ischemic brain. Translation will therefore require confirmation of ZO-1 molecular states and causal relevance in human BBB systems and patient-level studies, together with clinically relevant reperfusion, comorbidity, and treatment-window paradigms.
SN - 2296-634X
ER -