Ischemic stroke lacks clinically proven cerebroprotectants, partly because candidate targets have not been evaluated with rigorous translational pipelines. The aim of this study was to perform a systematic review about the potential role of the brain-enriched JNK3 signaling as a therapeutic target for acute ischemic stroke. A PRISMA-guided systematic search of PubMed, EMBASE and Scopus was performed up to October 2024. The research was limited to original research articles published in extenso on Institute for Scientific Information (ISI) Journals and written in English. Fifty-six studies met the inclusion criteria, all preclinical with a predominance for rodent models of global transient ischemia, with sparse representation of focal or large-animal models. Although the heterogeneous outcomes of the included studies, convergent evidence showed that JNK3 drives post-ischemic injury through (i) GluR6/NMDAR-PSD-95-MLK3 excitotoxic scaffolds, (ii) ASK1-initiated oxidative cascade, (iii) mitochondrial Bax/cytochrome-c apoptosis, (iv) ceramide synthesis and autophagy dysregulation, and (v) release from PI3K-AKT or HO-1 scaffold brakes. Collectively, literature supports JNK3 as a pleiotropic, druggable hub whose early blockade affords robust cerebroprotection, but translation into the clinical settings will require isoform-selective, brain-penetrant compounds evaluated in experimental conditions that more closely mirror clinical reality. Speculatively, future advances may derive from highly specific JNK3 inhibitors capable of targeting vulnerable neuronal populations within ischemic regions. When combined with optimized delivery systems and personalized therapeutic strategies, such agents may ultimately contribute to redefining the cerebroprotective landscape in stroke therapy.
Keywords: Acute ischemic stroke; Cerebral ischemia/reperfusion; Cerebroprotection; JNK3; Signal transduction.
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