ATF3 mediates high-salt diet-induced exacerbation of ischemic stroke: therapeutic potential of theta-burst stimulation

Acute ischemic stroke (AIS), a high-risk condition associated with significant morbidity and disability, could be further exacerbated by a high-salt diet (HSD). Although intermittent theta-burst stimulation (iTBS) is a clinically effective rehabilitation modality, its neuroprotective mechanisms remain unclear. This study aimed to elucidate the pathways through which HSD exacerbates early AIS injury, identify potential biomarkers, and assess the impact of iTBS intervention. First, bioinformatics techniques were employed to identify core genes associated with early ischemia and differentially expressed microglial genes (DEMGs) in mice subjected to middle cerebral artery occlusion (MCAO) with or without HSD. Subsequently, key pathways enriched among these DEMGs were elucidated. Next, co-expressed genes linked to HSD-exacerbated AIS mechanisms were selected as potential biomarkers and validated in vivo and in vitro. Finally, iTBS effects on biomarker expression were evaluated. As a result, integrative bioinformatics analysis implicated ATF3 as a potential biomarker for HSD-exacerbated AIS injury, mechanistically linked to HSD-induced microglial apoptosis. Consistently, HSD significantly upregulated ATF3 expression in both in vivo and in vitro AIS models. Furthermore, iTBS intervention significantly downregulated ATF3 expression within the HSD-exacerbated AIS context. Critically, iTBS also specifically downregulated ATF3 expression notably within hippocampal microglia of HSD-fed MCAO mice. Collectively, these findings suggest ATF3 serves as a potential biomarker for the combined injury induced by HSD and AIS and represents a promising therapeutic target for iTBS.