Cerebrovascular diseases are the leading cause of death globally, with approximately one-fourth of cerebrovascular deaths attributed to the rupture of cerebral aneurysms (CA) (Inagawa, 2022). CA is characterized by abnormal dilation or bulging in the cerebral arteries caused by localized arterial enlargement. They are primarily marked by the degradation of the local arterial wall structure, the loss of the internal elastic lamina, and rupture of the media layer (Takeda et al., 2022). CA can lead to subarachnoid hemorrhage (SAH) or fatal vascular rupture, with a mortality rate of approximately 50 % (Bakker et al., 2023). CA most commonly occur at large arterial branches or bifurcations of the basal cerebral arterial circle, with a higher frequency on the proximal side (Roessler et al., 2011). Current research on CA is primarily focused on clinical applications such as surgical techniques, timing of surgery, and embolic materials (Pescatori et al., 2022). The pathogenesis of aneurysms involves genetic factors, hemodynamic influences, and acquired degenerative alterations in the arterial wall (Texakalidis et al., 2019). Among these, arteriosclerosis and the chronic inflammatory response play a crucial role in the formation of CA (Wen et al., 2022; Frosen et al., 2019). Proteases, such as matrix metalloproteinases (MMPs), produced by macrophages, lymphocytes, and other cells involved in the inflammatory response, can degrade elastic and collagen fibers in the vascular wall. This degradation contributes to the development, expansion, and eventual rupture of aneurysms (Chu et al., 2015). Vascular remodeling plays a critical role in the formation of CA. Changes in hemodynamics or genetic factors can lead to abnormal remodeling processes in the local arterial walls, resulting in structural weaknesses. In these compromised regions, there may be a reduction in vascular smooth muscle cells and elastic fibers, along with increased activity of MMPs. These processes promote the degeneration and dilation of the vascular wall, ultimately leading to CA formation (Frosen et al., 2019; Penn et al., 2014). Additionally, endothelial dysfunction in CA formation may trigger inflammatory responses and cause structural weaknesses in the vascular wall, facilitating the development of aneurysms (Sheinberg et al., 2019). Modulating the release of MMPs and macrophage infiltration, and thereby mitigating inflammatory responses, could offer a promising avenue for treating CA.

Phoenixin (PNX) is a highly conserved active peptide that was first identified by Yosten in 2013 (Billert et al., 2020). PNX is derived by proteolytic processing from the C-terminal region of the small integral membrane protein 20 (Smim20), which plays a role in the assembly of the cytochrome c oxidase complex. The two primary subtypes of PNX are PNX14 and PNX20. PNX exhibits widespread expression across various tissues in rats, with notable concentrations in the hypothalamus, including the paraventricular and supraoptic nuclei, zona incerta, arcuate nucleus, dorsal and ventromedial regions, median eminence, and anterior and posterior pituitary gland. It is also present in the spinal cord, heart, thymus, gastrointestinal tract, pancreatic islets, adipose tissue, ovaries, and skin layers, with PNX-20 being predominant in the brain and PNX-14 more common in the spinal cord and heart (Liang et al., 2022). Recent research has indicated that PNX exerts multiple functions via GPR173, a member of the Super Conserved Receptor Expressed in the Brain (SREB) family. Downregulation of GPR173 mRNA expression through siRNA interference diminished the stimulatory effect of PNX on luteinizing hormone (LH) secretion triggered by gonadotropin-releasing hormone (GnRH) in female rats (Stein et al., 2016). Early studies discovered that PNX-14 plays a crucial role in maintaining normal reproductive function (Stein et al., 2016; Yosten et al., 2013). Subsequent research has shown that PNX-14 fosters appetite, enhances memory, and mitigates anxiety (Yosten et al., 2013; Jiang et al., 2015a). Recent studies increasingly support the anti-inflammatory and anti-apoptotic cytoprotective effects of PNX-14. Wang's research demonstrated that PNX-14 can mitigate LPS-induced endoplasmic reticulum stress, inflammasome activation, and the secretion of pro-inflammatory cytokines IL-1β and IL-18 in astrocytes. Furthermore, the protective impact of PNX-14 in attenuating neuroinflammation in mice is negated by the deletion of the GPR173 receptor (Wang et al., 2020). Additionally, PNX-14 has been shown to inhibit hypoxia/reoxygenation injury in cerebral vascular endothelial cells, with the underlying mechanism involving the suppression of NF-κB and a decrease in the production of ROS, IL-6, and TNF-α (Zhang and Li, 2020). Recent evidence indicates that PNX-14 exhibits neuroprotective properties in various animal models (Yu et al., 2022). Akdu S reported a significant reduction in PNX-14 levels among patients with hypertension (Akdu et al., 1992). However, it is currently unknown whether PNX-14 possesses a beneficial effect in CA. Therefore, the therapeutic role and underlying mechanism of PNX-14 in CA were explored in this study.