Stroke is a leading cause of disability worldwide, with its epidemiology marked by a high incidence and prevalence, particularly in older populations [1]. The complexity of stroke arises from its diverse etiologies, ranging from ischemic to hemorrhagic events, which lead to distinct pathophysiological mechanisms [2]. A critical feature of stroke pathology is the disruption of the blood-brain barrier (BBB), which increases susceptibility to secondary brain injury [3]. Following stroke, neuronal death occurs through a combination of necrosis and apoptosis, and a cascade of neuroinflammatory responses exacerbates tissue damage [4]. Among the various factors contributing to stroke damage, neuroinflammation has emerged as a central player. Despite the growing understanding of its role, there are limited pharmacological treatments targeting neuroinflammation in stroke, highlighting the need for novel therapeutic approaches [5].

One of the key features of stroke-induced neuroinflammation is the activation and polarization of microglia, the resident immune cells in the central nervous system [6]. Post-stroke, microglia undergo significant phenotypic changes, displaying heterogeneity in their responses. While some microglia adopt pro-inflammatory roles, contributing to neurodegeneration, others exhibit anti-inflammatory properties that aim to repair tissue and restore homeostasis [7]. This dichotomy plays a crucial role in determining the extent of injury and recovery following stroke. Importantly, understanding how these microglial responses are regulated is essential for developing strategies to modulate their function therapeutically.

Sirtuin 1 (SIRT1) and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) are two critical molecular players in the regulation of neuroinflammation [8]. SIRT1, a NAD + -dependent deacetylase, has been shown to modulate inflammatory pathways and neuronal survival [9]. It interacts with NF-κB, a central mediator of the inflammatory response, to influence the balance between pro- and anti-inflammatory signals [10]. The intricate interaction between SIRT1 and NF-κB post-stroke suggests that these pathways could be therapeutic targets for controlling neuroinflammation and promoting neuronal repair [11].

In recent years, apelin-13, a peptide involved in various physiological processes, has gained attention for its potential role in brain diseases [12]. Recent studies have shown that different apelin isoforms exhibit biased signaling effects on the APJ receptor, a class A G protein-coupled receptor. Specifically, apelin-13, apelin-17, apelin-36, and pGlu1-apelin-13 have been demonstrated to differentially activate G protein-dependent pathways (such as cAMP inhibition, calcium mobilization, and ERK phosphorylation) as well as β-arrestin-dependent signaling cascades (including GRK-mediated recruitment of β-arrestin1/2 and AP2) [13]. These isoforms not only vary in their signal transduction potency but also selectively phosphorylate specific serine residues at the APJ C-terminus, such as Ser335 and Ser339, thereby differentially modulating β-arrestin recruitment, receptor internalization, and downstream signaling [14]. These findings suggest that apelin isoforms act as biased ligands, inducing distinct intracellular responses through isoform-specific modulation of APJ activity. Its precise mechanism of action in neuroinflammation and stroke is still under investigation, but emerging evidence suggests it may modulate neurovascular function and cellular responses to ischemic injury [15]. While the full therapeutic potential of apelin-13 in stroke remains unclear, its role in brain disease warrants further exploration, especially as it may provide a novel avenue for managing neuroinflammation.

In this study, we aim to explore the roles of SIRT1, NF-κB, and apelin-13 in stroke-induced neuroinflammation. By investigating their interactions and functional outcomes, we hope to provide insight into new therapeutic strategies for managing neuroinflammation and improving recovery after stroke.