Subarachnoid hemorrhage (SAH), a common manifestation of ruptured brain aneurysm, is one of the most devastating cerebrovascular diseases, as evidenced by high disability and mortality rates across the globe (Long et al., 2017; Collaborators, 2019). SAH is further associated with various complications, which may lead early brain damage and a plethora of secondary effects such as increased intracranial pressure, brain displacement, as well as destruction of brain tissue by intracranial hemorrhage (Macdonald, 2014). The latter complications are particularly important as the poor prognosis of SAH is primarily attributed to early brain injury (EBI) (Fujii et al., 2013). EBI often involves several physiological derangements, including increased brain swelling and edema, neuronal apoptosis, etc. (Sehba et al., 2012). Despite numerous advances, SAH continues to be associated with high morbidity and mortality rates, accompanied by poor outcomes owing to EBI (Smith and Citerio, 2015). Therefore, a deeper understanding of the underlying molecular mechanisms related to EBI could pave the way for new prevention strategies and therapeutic methods for EBI following SAH.

microRNAs (miRNAs), small non-coding RNAs ranging from 19 to 25 nucleotides in length, are well-known for their ability to regulate the expression of their target genes (Lu and Rothenberg, 2018). miRNAs are also capable of targeting multiple mRNAs, which, in turn, modulates diverse cellular processes, including cell proliferation and apoptosis (Carroll et al., 2013; Mohr and Mott, 2015). Unsurprisingly, alterations in miRNAs are implicated in the pathogenesis of various cardiovascular diseases, including SAH (Lai et al., 2017). One such miRNA, namely miR-26b, was reported to function as a potential biomarker in the development of SAH (Qin et al., 2019). Initial microarray analysis in the current study indicated Krüppel-like factor 4 (KLF4) as a target gene of miR-26b. Similarly, the work of Sahu et al. have also confirmed that KLF4 is targeted by miR-26a, and its participation in the process of inflammation (Sahu et al., 2017). KLF4 consists of a zinc finger structure and belongs to the Krüppel-like factor family of transcription factors (Cuttano et al., 2016), and there is much evidence to suggest that KLF4 is implicated in the progression of SAH (Kikkawa et al., 2017). Nevertheless, the effect of KLF4 linked to the development of EBI after SAH remains to be explored. Meanwhile, KLF4 is further known to bind to signal transducer and activator of transcription 3 (STAT3) to regulate its transcription activity (Qin et al., 2013). STAT3 represents a member of the STAT protein family which exerts crucial role in the regulation of cell processes covering apoptosis, angiogenesis, and proliferation (Verhoeven et al., 2020). Interestingly, numerous studies have further explored the roles of STAT3 in inflammatory responses in SAH-induced EBI (Wei et al., 2017). Furthermore, STAT3 exerts a positive regulatory effect on the expression of high mobility group box chromosomal protein 1 (HMGB1) (Fang et al., 2016). HMGB1 belongs to a ubiquitous nuclear protein capable of functioning as a mediator in inflammatory reaction (Andersson and Tracey, 2011). Accumulating evidence has also elucidated that HMGB1 could trigger inflammation, thereby acting as an inflammatory mediator to promote the progression of SAH (Sun et al., 2014). In lieu of the above evidence, we speculated that miR-26b may influence EBI after SAH via regulation of the KLF4/STAT3/HMGB1 axis. Accordingly, the current study sought to testify this hypothesis to provide a better understanding of molecular mechanisms of EBI following SAH, in an effort to uncover a novel therapeutic target for its treatment.