Gastric ulcer is a common gastrointestinal condition with substantial worldwide health impacts, characterized by erosions in the gastric mucosa that can progress to serious complications such as hemorrhage and perforation [1], [2]. The development of gastric ulcers involves a complex interplay between damaging factors, like gastric acid, and protective mechanisms, including mucosal blood flow and antioxidant activity [3]. Excessive ethanol consumption is a key contributor, precipitating ethanol-induced gastric ulcer through mechanisms that involve robust inflammatory responses and oxidative stress [4]. Inflammatory processes, mediated by cytokines such as IL-6 and TNF-α, coupled with excessive reactive oxygen species (ROS) production, compromise mucosal integrity, leading to cellular apoptosis and hindered repair [5]. Although current treatments, including proton pump inhibitors and H2 receptor antagonists, offer symptomatic relief, they often fall short in addressing the underlying inflammatory and oxidative stress components, resulting in inadequate efficacy and high recurrence rates [6]. Thus, there is a pressing need for new protective agents that target the fundamental pathological pathways, particularly the interconnected inflammatory and oxidative stress mechanisms, to achieve more effective gastroprotection [7].

The binding of advanced glycation end-products (AGE) to their receptor (RAGE) is a key pathogenic driver of pro-inflammatory signaling, implicated in the pathology of numerous chronic diseases [8]. This interaction, along with ROS overproduction, triggers the activation of downstream signaling pathways, predominantly the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) cascades. These cascades upregulate the expression of inflammatory mediators such as cytokines and inducible nitric oxide synthase (NOS2), thereby exacerbating tissue injury [9]. Excessive and sustained levels of nitric oxide generated by NOS2 activation, particularly under oxidative stress conditions, result in the formation of reactive nitrogen species, notably peroxynitrite (ONOO−), through the rapid reaction of NO with superoxide anion, which amplifies oxidative damage and cellular apoptosis [10], [11]. However, the biological role of NOS2 is highly context-dependent and not universally detrimental; in some conditions, iNOS activation can be protective. This protective effect may be underpinned by genetic factors, such as the (CCTTT)ₙ pentanucleotide repeat, which enhances IL-1β-induced iNOS transcription, with the 14- and 15-repeat alleles being more potent than the 12-repeat allele [12]. In this context, the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway functions as the primary cellular defense mechanism against oxidative insults [13], [14]. Upon activation by cellular stress, NRF2 translocates to the nucleus and orchestrates the transcription of a suite of cytoprotective genes, including heme oxygenase-1 (HO-1) and superoxide dismutase 2 (SOD2), which are instrumental in neutralizing ROS and mitigating oxidative damage [15]. Notably, inflammation and oxidative stress are intricately interconnected in a self-perpetuating vicious cycle: inflammatory processes generate excessive ROS, which in turn amplify pro-inflammatory signaling, creating a feed-forward cycle that drives tissue damage [16]. This inflammation-oxidative stress axis is therefore considered a fundamental driver underlying the onset and progression of a wide spectrum of chronic pathologies.

To tackle this, triazole derivatives have gained interest for their diverse pharmacological effects, including anti-inflammatory and antioxidant activities [17]. Among them, the novel synthesized compound 5-(4-methoxyphenyl)-1-phenyl-1H-1,2,3-triazole (MPTA) emerges as a promising candidate. The 1,2,3-triazole versatile scaffold is prominent in drug discovery due to its hydrogen-bonding and π-stacking abilities, which facilitate binding to biological macromolecules [18], [19]. It is worth noting that our previous research identified a phenyl-1H-1,2,3-triazole derivative, structurally similar to MPTA, which showed efficacy in a mouse model of ulcerative colitis, further supporting the therapeutic potential of this scaffold [20]. Based on this premise, this study focuses on elucidating MPTA's role in alleviating ethanol-induced gastric ulcer, thereby filling the knowledge void in multi-pathway protective strategies.

Therefore, this study employs an integrated methodology combining network pharmacology, proteomic analysis, and experimental validation in mouse models and gastric epithelial cells to investigate whether MPTA protects against ethanol-induced gastric ulcer to inhibit the AGE-RAGE pathway, thereby mitigating inflammation and oxidative stress. We anticipate that our findings will provide novel insights into the gastroprotective mechanisms of triazole derivatives and underscore the protective significance of the NOS2-AGE-RAGE axis in gastric ulcer management.