# Deciphering the disease ecosystem of ischemic stroke via multi-omics and prospects for therapeutic strategies

## TL;DR

This paper redefines ischemic stroke as a complex 'disease ecosystem' and proposes new therapeutic strategies targeting the whole system rather than single components.

## Contribution

Introduces the concept of 'ecosystem engineering' as a novel therapeutic framework for ischemic stroke.

## Key findings

- Ischemic stroke involves five interconnected features like cellular collapse and immune miscommunication.
- Current single-target therapies fail due to the complex, dynamic nature of the disease ecosystem.
- Proposes temporally adaptive and network-coordinated interventions for precision neural repair.

## Abstract

Ischemic stroke (IS) remains a leading cause of disability due to the translational failure of single-target therapies, underscoring the limitations of the traditional neuron-centric view. This review proposes a paradigm shift by conceptualizing IS as a dynamically evolving “disease ecosystem.” We integrate multi-omics evidence to delineate five interconnected core features—cellular identity collapse, inflammatory-reparative imbalance, neurovascular unit disintegration, brain-peripheral immune miscommunication, and extracellular matrix scarring—that form a pathological logic axis driving disease progression. Based on this systemic understanding, we advance the novel therapeutic strategy of “ecosystem engineering,” which emphasizes temporally adaptive, spatially precise, and network-coordinated interventions. This framework aims to overcome current therapeutic bottlenecks and usher in a new era of precision neural repair.

Decoding the ischemic stroke disease ecosystem: from systemic collapse to therapeutic remodeling. The graphical abstract conceptualizes the paradigm shift from a traditional neuron-centric view to a holistic “disease ecosystem” perspective in ischemic stroke. The left panel (Ecosystem Homeostasis) symbolizes the balanced multicellular community in a healthy brain. The central panel (Cascade Collapse) depicts the five interconnected core features (cellular identity collapse, inflammation-repair imbalance, NVU disintegration, brain-peripheral immune miscommunication, and ECM scarring) that drive ecosystem failure following ischemia. The right panel (Therapeutic Ecosystem Engineering) illustrates the proposed intervention strategy, guided by three core principles: temporally dynamic, spatially precise, and network-coordinated interventions, aimed at steering the damaged ecosystem from a pathological state toward functional recovery. “Graphical Abstract” created in BioRender. Hong, Zhi (https://BioRender.com/hj9yl80) is licensed under CC BY 4.0.Corresponding license: Publication License Jan-13-2026.pdf (Agreement number: JI298E4MNO).
Infographic contrasting single-target approaches and ecosystem-based strategies for ischemic stroke. It illustrates failures of neuron-centric views, highlights issues like cellular collapse, inflammatory imbalance, immune miscommunication, NVU disintegration, ECM scarring, and advocates for coordinated temporal and spatial intervention strategies to rebalance the disease ecosystem.

Decoding the ischemic stroke disease ecosystem: from systemic collapse to therapeutic remodeling. The graphical abstract conceptualizes the paradigm shift from a traditional neuron-centric view to a holistic “disease ecosystem” perspective in ischemic stroke. The left panel (Ecosystem Homeostasis) symbolizes the balanced multicellular community in a healthy brain. The central panel (Cascade Collapse) depicts the five interconnected core features (cellular identity collapse, inflammation-repair imbalance, NVU disintegration, brain-peripheral immune miscommunication, and ECM scarring) that drive ecosystem failure following ischemia. The right panel (Therapeutic Ecosystem Engineering) illustrates the proposed intervention strategy, guided by three core principles: temporally dynamic, spatially precise, and network-coordinated interventions, aimed at steering the damaged ecosystem from a pathological state toward functional recovery. “Graphical Abstract” created in BioRender. Hong, Zhi (https://BioRender.com/hj9yl80) is licensed under CC BY 4.0.Corresponding license: Publication License Jan-13-2026.pdf (Agreement number: JI298E4MNO).