Work

Zonula occludens-1 at the ischemic blood–brain barrier: mechanisms of disruption, functional significance, and experimental modulation

Year: 2026

Type: review

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.

Source: Frontiers in Cell and Developmental Biology

DOI: 10.3389/fcell.2026.1967401

Authors: Bosi Zhou, Zhihan Wang, Xuefeng Jing, Bing Xu, Xue Qin

Institution: Shenyang Pharmaceutical University

Language: English

Topic: Barrier Structure and Function Studies

Subfield: Neurology

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801