TAZ alleviates ischemic stroke injury by activating Foxo1: Usp1-mediated deubiquitination is the pivotal mechanism.

BACKGROUND

The pathological progression of ischemic stroke (IS) is closely associated with oxidative stress and neuronal apoptosis, yet current therapeutic strategies remain substantially limited. The critical role of the transcriptional coactivator TAZ in this process, particularly in modulating oxidative damage, is not well defined.

METHODS

By integrating a middle cerebral artery occlusion (MCAO) mouse model with an oxygen-glucose deprivation/reoxygenation (OGD/R) neuronal injury model, this study reveals the critical role of the transcriptional coactivator TAZ in modulating oxidative damage via Foxo1 and by coordinating with the deubiquitination activity of ubiquitin-specific protease 1 (Usp1).

RESULTS

Single-cell RNA sequencing combined with transcriptomic datasets demonstrated spatiotemporal dynamics of TAZ expression in ischemic brain tissues, showing significant downregulation at 24 h post-reperfusion. This decline inversely correlated with peaks of oxidative stress markers (glutathione peroxidase [GSH-px], superoxide dismutase [SOD]) and pro-inflammatory cytokines (interleukin-6 [IL-6], interleukin-1β [IL-1β]). Enhanced TAZ expression reduced cerebral infarct volume, improved cerebral blood flow, and ameliorated neurological and cognitive deficits. Mechanistically, TAZ promoted Foxo1 transcriptional activity, upregulating antioxidant genes SOD2 and catalase, thereby suppressing reactive oxygen species (ROS) accumulation and neuronal apoptosis.

CONCLUSIONS

Usp1 counteracted TAZ ubiquitination to stabilize its protein levels, synergistically reinforcing Foxo1 DNA-binding capacity. The coordinated action of Usp1 and TAZ attenuated oxidative stress, neuronal death, and infarct progression. These findings establish the Usp1-TAZ-Foxo1 axis as a critical regulator of antioxidant defense and neuronal survival, providing a theoretical foundation for targeted therapeutic strategies in IS.