Stroke is currently the second most prominent cause of mortality worldwide, contributing to a substantial burden of disease as measured by disability adjusted life year totaling around 143 million person-years. This places stroke as the third highest contributor to the global burden of disease (Global Burden of Disease Study 2019, 2020). Moreover, stroke stands as the primary cause of mortality and the foremost contributor to years of life lost due to disease in China (Wu et al., 2019). Cerebral ischemia and hypoxia result in persistent and irreversible damage to brain cells. Initially, shortly after the onset of a stroke, neuronal death occurs due to severe hemorrhage or ischemia. Subsequently, in the hours or days following the stroke, acute neuronal death induces an inflammatory response, which further contributes to the loss or death of additional neurons. This exacerbates the patient's neurological deficits and initiates a cascade of pathophysiological mechanisms, including excitotoxicity (Bahr-Hosseini et al., 2023), oxidative and nitrosative stress (Chamorro et al., 2016), inflammation (Pinson et al., 2023), and disruption of the blood-brain barrier (Wang et al., 2023). These pathophysiological mechanisms can further cause other complications, such as post-stroke depression (Song et al., 2015), cognitive impairment (Dong et al., 2022), post-stroke epilepsy (Phan et al., 2022), and post-stroke dysphagia (Jiang et al., 2023) (Fig. 1). These symptoms not only reduce the quality of life of stroke patients, cause functional disability, increase long-term mortality, but also increase the economic burden of society and patients' families (Miranda et al., 2018). Despite significant advancements in thrombolysis and thrombectomy techniques, the treatment of stroke remains a challenge due to the restricted time frame for intervention. Consequently, a considerable number of patients are unable to undergo vascular recanalization therapy, making the achievement of neuroprotection in stroke cases an ongoing obstacle (Bangar et al., 2024).

A neuropeptide is a naturally occurring bioactive chemical that is present in nerve tissue and is capable of modulating the functioning of the nervous system. The material in question possesses unique attributes, namely a low content, high activity, and a broad range of complex functions (Lühder et al., 2009). Numerous neuropeptides have been discovered through extensive research, including but not limited to orexin (Berteotti et al., 2021), motilin (Mori et al., 2023), neuropeptide Y (NPY) (Chen et al., 2023b), and substance P (Safwat et al., 2023). These neuropeptides have been the subject of extensive investigation due to their significant roles in controlling food intake, enhancing metabolism and neuromodulation (Ishioh et al., 2024; Karsan et al., 2023; Vu et al., 2023). NPY is a neurotransmitter that exhibits a widespread distribution throughout the central nervous system (CNS). The initial identification and isolation of this compound occurred in 1982 by Tatenoto et al. through the examination of pig brain tissue (Tatemoto et al., 1982). Subsequently, its involvement has been implicated in various pathological conditions, including cerebrovascular illness (Sun et al., 2021), Parkinson's disease (Behl et al., 2022), Alzheimer's disease (Kim et al., 2020), hypertension (Tian et al., 2023), and cardiac remodeling (Stadiotti et al., 2021).

This article provides analysis of the signaling pathways associated with NPY and its involvement in stroke risk factors, expression levels, and complications. The aim is to gain a thorough understanding of the potential clinical applications of NPY in the treatment of stroke, identification of stroke and its related complications, and assessment of prognosis.

The first purification and proposal of the endogenous bioactive polypeptide from pig brain was conducted by Tatemoto et al. in 1982 (Tatemoto et al., 1982). This polypeptide, known as NPY, exhibits a significant sequence similarity to both casein peptide and pancreatic polypeptide, indicating its membership in the same peptide family (Chen et al., 2023a). The gene in question is situated on chromosome 7 of the human genome, specifically at the locus 7p15.1 (Tatemoto et al., 1982). The coding length of the gene is 8.1 kb, containing 4 exons and 3 introns (Tatemoto et al., 1982). And NPY is a peptide consisting of 36 amino acids with a molecular weight of approximately 4.2 kilodaltons (Larhammar, 1996). Its structural characteristics include two hydrophobic regions. The first hydrophobic region comprises eight amino acid residues located at the N-terminal, forming a polyproline single helix structure. The second hydrophobic region follows the first one and consists of 5–6 amino acid residues (Langley et al., 2022). Furthermore, NPY possesses many secondary structure features, such as β angle and α-helix, contributing to its overall stability (Park et al., 2022). The diversity within the structure of NPY allows it to interact with various receptors, leading to physiological effects on the digestive system, vascular system, hypothalamus, and other biological systems (Holzer et al., 2012). Furthermore, numerous studies have provided confirmation about the great similarity observed in NPY gene sequences and amino acids across various species (Yu et al., 2022).

Within the human body, various tissues possess the capability to synthesis and produce NPY within the endoplasmic reticulum (Brothers and Wahlestedt, 2010). Examples of such tissues include sympathetic nerves and platelets, among others (Businaro et al., 2018; Zukowska-Grojec et al., 1998). NPY is synthesized within the endoplasmic reticulum and subsequently undergoes transportation and storage within the Golgi complex, which is located in close proximity but in the opposite direction (Pain et al., 2022). The precursor protein is released into the extracellular space through enzymatic digestion and post-translational modification when the body requires it (Pain et al., 2022). NPY exhibits a broad distribution in the central and peripheral neurological systems, as well as in various tissues, organs, and glands of both humans and animals (Bale and Doshi, 2023; Mahar et al., 2016; Marcos and Coveñas, 2022; Silva et al., 2002). In the CNS, it exists in many brain regions and neuron groups, including hypothalamus, amygdala, hippocampus, pituitary gland and sympathetic ganglia (Robinson and Thiele, 2017). The secretion of this substance occurs in conjunction with traditional neurotransmitters, such as γ-aminobutyric acid (Madadi et al., 2023) and noradrenaline (McDowell et al., 2023).

Up to now, seven different NPY receptors, including Y1R, Y2R, Y4R, Y5R, Y6R, Y7R, and Y8R (Yi et al., 2018), have been identified in vertebrates, of which four (Y1R, Y2R, Y4R and Y5R) receptors have been confirmed to play a role in humans, and all of them are G-protein-coupled receptors (Brothers and Wahlestedt, 2010). In human central and peripheral nervous system, neuropeptide Y receptor is encoded by different genes and shows different tissue distribution. Y1R, Y2R and Y5R have high hydrophobicity and are all located on chromosome 4 (Czarnecka et al., 2019), Y4R gene is located on chromosome 10 and consists of 375 amino acids (Sainsbury et al., 2010). And, Y4R shares significant homology with Y1R and, in conjunction with the Y1R and Y2R receptors, regulates organismal function (Kang et al., 2019; Sainsbury et al., 2003). The NPY receptors exhibit a broad distribution throughout several anatomical regions, including the hypothalamus, sympathetic nerve terminals, spinal cord, tonsils, vascular smooth muscle, and other tissues (Yi et al., 2018). These receptors play a significant role in modulating diverse physiological activities such as hunger regulation (Zhang et al., 2012), hyperalgesia (Gupta et al., 2018), epilepsy (Cattaneo et al., 2020), vascular disorders (Zheng et al., 2021), anti-anxiety responses (Rana et al., 2022), and other related processes (Zhang et al., 2021)(Fig. 2).