R788 is Associated with Neuroprotective Effects in Experimental Ischemic Stroke Models via Modulation of the STAT1/Nrf2/GPX4 Axis

Background: Ischemic stroke, the most prevalent form of cerebrovascular disease, stands as a leading global cause of both disability and mortality. Oxidative stress damage is a critical pathological mechanism in stroke, and regulated cell death may be an effective therapeutic target for treating ischemic stroke. This work provides the first evidence that R788, a small-molecule inhibitor of spleen tyrosine kinase, exerts therapeutic efficacy in ischemic stroke, thereby unveiling a novel mechanistic basis and potential strategy for intervention. Methods: The antioxidant defense and anti-apoptotic effects of R788 were assessed in a middle cerebral artery occlusion (MCAO) animal model and an H 2 O 2 -induced SH-SY5Y cell model of IS. A total of 24 male C57BL/6 mice were randomly divided into 4 groups (n=6). Then we measured the intracellular Fe 2+ concentration and lipid peroxidation levels, and the expression of the STAT1/Nrf2/GPX4 pathway was evaluated in the MCAO animal model and the cell model. Results: The results showed that both in the animal and cell models, the R788-treated group had an increased number of surviving SH-SY5Y cells compared to the control group. Additionally, the R788 group showed the inhibition of p-STAT1 and suppressed ferroptosis. We confirmed that R788 treatment alleviated oxidative stress damage by inhibiting ferroptosis-related pathways, thereby promoting cell survival. In summary, R788 demonstrated neuroprotective effects against ischemia-induced neural injury in both in vivo and in vitro models. Conclusion: Our workss suggest that R788 alleviate localized ischemic injury and oxidative stress damage by regulating STAT1/Nrf2/GPX4 pathways. These findings indicate that R788 shows potential for the treatment of IS. Keywords: R788, ischemic stroke, ferroptosis, STAT1