Ulcerative colitis (UC) is a prevalent inflammatory bowel diseases (IBD) characterized by abdominal pain, diarrhea, and rectal bleeding. Histological and endoscopic findings typically show intestinal erosion, lamina propria cell infiltration, lymphocyte aggregation, and crypt abscesses [1]. Epidemiological surveys indicate that, in addition to Western countries with high incidence rates, the incidence of IBD is also rising in Asia and Latin America. Although the underlying causes of UC are complex and not fully understood, it is well established that genetic and environmental factors, including diet, lifestyle, and mental health, increase the risk of UC [2]. Despite the availability of a variety of immunomodulatory therapies, UC remains incurable. Approved treatments, such as 5-aminosalicylic acid, corticosteroids, immunosuppressants, and biological agents, are used at different stages of the disease to control symptoms [3]. However, the efficacy of these treatments is limited, and surgery may eventually be required to remove part or even the entire colon [2,4]. Therefore, there is an urgent need for the development of new and effective drugs to treat UC.

In ulcerative colitis (UC), the immune environment is characterized by dysregulated immune responses, marked by an imbalance between pro-inflammatory and anti-inflammatory cytokines, along with alterations in the gut microbiota [5]. The immune system plays a crucial role in UC pathogenesis, with elevated levels of Th17 cells and inflammatory cytokines such as IL-17 and TNF-α driving the disease [6]. Disruption of the intestinal barrier further amplifies the inflammatory cascade, leading to increased infiltration of immune cells into the gut. Additionally, oxidative stress and ferroptosis contribute to epithelial cell death and tissue damage, exacerbating the inflammation [7]. The gut microbiota also plays a pivotal role, with an increase in pathogenic bacteria and a decrease in beneficial microbes, such as Bacteroides and Firmicutes, which intensify the inflammatory process. These immune dysregulations are further complicated by alterations in both the innate and adaptive immune systems. Innate immune cells, such as dendritic cells, macrophages, and epithelial cells, can detect pathogens and initiate inflammatory responses through pattern recognition receptors (PRRs), triggering the release of cytokines, chemokines, and the recruitment of inflammatory cells [8,9]. Macrophages as highly heterogeneous tissue-resident immune cells, play a protective role by responding to danger signals, phagocytosing pathogens, and secreting inflammatory mediators, have demonstrated potential for alleviating UC symptoms and modulating the immune environment [10].

When macrophages are stimulated by pathogens, inflammatory responses, and certain physical and chemical agents, they undergo a differentiation process that depends on their environmental context. It is generally believed that macrophages polarize into two principal phenotypes: M1 and M2, M1 macrophages are thought to participate in pro-inflammatory responses, while M2 macrophages are recognized for their anti-inflammatory properties [11]. Previous studies have shown that lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) induce macrophages to differentiate into M1 phenotype, promote Th1-type immune response, and secrete a large amount of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase, and tumor necrosis factor-α (TNF-α) [12]. M1 macrophages and secretion of pro-inflammatory factors are implicated in the exacerbation of UC, while M2 phenotype is posited to promote tissue repair and resolve inflammation, alleviating the pathological manifestations of UC [13], this indicates that macrophages play a pivotal role in the pathogenesis of UC.

The Notch signaling cascade is a highly conserved pathway that plays a pivotal influence on cellular processes such as proliferation, differentiation, and fate determination. This signaling mechanism is initiated by the Notch protein, which acts as a receptor for a range of the transmembrane ligands, including Jagged1, Jagged2, and Delta-like (Dll1, Dll3, Dll4) proteins. Upon ligand binding, the Notch receptor undergoes proteolytic cleavage by a secretase enzyme. The intracellular domain of Notch then translocates to the nucleus, where it modulates the expression of specific target genes, such as hairy and enhancer of split (Hes1) [14]. Within the immune system, the Notch signaling pathway is involved in modulating macrophage polarization. Stimulating macrophages with pro-inflammatory factors not only induces M1 macrophages but also leads to the upregulation of Notch pathway components and the subsequent activation of canonical Notch signaling [15]. Studies have shown that in diabetic nephropathy, the interplay between Notch and NF-κB signaling within macrophages facilitates macrophage polarization, increases the secretion of inflammatory mediators, and exacerbates tissue injury [16]. This demonstrates the close association between Notch signaling activation and the M1 macrophage phenotype. However, it remains unclear whether Notch signaling regulates macrophage activation in UC [17].

Building on our previous research demonstrating that artemether (ART) can regulate macrophage polarization in the liver [18], and recognizing the close relationship between macrophage polarization and Notch signaling, this study aims to explore the therapeutic potential of ART in ulcerative colitis (UC). Specifically, we seek to investigate whether ART can modulate macrophage polarization in UC, with a particular focus on the role of Notch signaling in this process. The findings from this study could provide valuable insights into the mechanisms by which ART exerts its anti-inflammatory effects, offering a basis for the development of novel therapeutic approaches for UC.