Nrf2-ARE signaling pathway-mediated protection in rat models of intracerebral hemorrhage with different volumes.

Intracerebral hemorrhage (ICH) is a severe subtype of stroke associated with high mortality and disability. With the global population aging, the incidence of ICH is increasing, highlighting the importance of understanding endogenous protective mechanisms. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway mitigates oxidative stress and inflammatory injury after ICH, but the influence of hemorrhage volume on this response remains unclear. Here, we established rat ICH models with varying hemorrhage volumes (25, 50, 75, and 100 µL) and assessed Nrf2/ARE pathway activation using histopathology, immunohistochemistry, immunofluorescence, Western blotting, and RT-qPCR. Oxidative stress markers and antioxidant enzyme activities were also evaluated. Bioinformatic analysis of public datasets identified NQO-1 as a key differentially expressed gene after ICH. Among all groups, the 50 µL model showed the strongest Nrf2 nuclear translocation, highest NQO-1 and HO-1 expression, reduced oxidative damage, and attenuated inflammatory responses. These findings suggest that moderate hemorrhage volume elicits optimal endogenous Nrf2/ARE activation, offering maximal neuroprotection. Clinically, this supports a stratified treatment approach: enhancing Nrf2/ARE signaling in moderate-volume ICH and considering surgical reduction of hematoma burden in large-volume cases before pharmacological activation. This study provides an experimental basis for integrating molecular pathway modulation into individualized ICH management.