Functional dyspepsia (FD) is a gastrointestinal disorder characterized by digestive symptoms, including upper abdominal pain, early satiety, and postprandial bloating. It is a chronic, persistent, and recurrent condition that not only affects the quality of life of patients but also imposes a significant economic burden on healthcare systems [1], [2], [3]. Currently, treatments such as acid suppressants and prokinetic agents are commonly used to alleviate the symptoms of FD. However, their overall efficacy remains limited, and their long-term use has been questioned [4]. As a result, the treatment and long-term management of FD remain significant challenges, highlighting the urgent need to better understand its pathogenesis and develop more effective therapeutic strategies. The etiology of FD is not yet fully understood. The traditional view has been that the main cause of FD is abnormal gastrointestinal motility. However, the correlation between motility disturbances and symptoms is weak, and effective treatment plans have not been established [5], [6]. Recent research has focused on gastrointestinal hypersensitivity, specifically abnormal pain signals triggered by chemical and/or mechanical stimuli and the role of duodenal mucosal immune microinflammation. These processes contribute to the release of pain mediators and gastrointestinal hypersensitivity [7], [8].

Immune factors play an important role in the pathogenesis of FD. The duodenum is a key site for the development of functional gastrointestinal symptoms, and post-infectious functional dyspepsia (PI-FD) is closely related to changes in local immune cells in the duodenum. In FD, the duodenal mucosal immune system presents a micro-inflammatory state, mainly characterized by the infiltration and activation of mast cells and eosinophils [9], [10], [11]. Lu et al. found that promoting M1 polarization of intestinal macrophages can suppress intestinal inflammation [12]. Pi et al. reported that ursodeoxycholic acid can inhibit intestinal inflammation caused by low birth weight by inducing macrophage polarization towards the M2 type [13]. In addition, studies have shown that in inflammatory bowel disease (IBD), immature macrophages accumulate and secrete pro-inflammatory cytokines, such as TNF, IL-1β, IL-6, and IL-23, during intestinal immune and inflammatory activation, further aggravating tissue damage [14], [15]. It is worth noting that targeted depletion of mature macrophages using diphtheria toxin can induce epithelial cell death, increase intestinal permeability, and promote the development of IBD [14]. These studies demonstrate that macrophages play an important role in maintaining normal function in the activation of gastrointestinal immunity.

Multiple studies have shown a strong association between PANoptosis and the progression of intestinal diseases [3]. As key immune cells, macrophages contribute to the pathogenesis of FD through PANoptosis. For example, macrophages can limit the spread and diffusion of pathogens through apoptosis, thereby affecting the inflammatory response and immune function of the gastrointestinal tract [16], [17]. Moreover, macrophage PANoptosis may also affect the motility and sensory function of the gastrointestinal tract. Gastrointestinal motility dysfunction is one of the important pathogenesis mechanisms of FD, and the PANoptosis process of macrophages may regulate gastrointestinal motility and sensation by altering the secretion of neurotransmitters and hormones in the gastrointestinal tract [18]. However, the underlying molecular mechanism is not yet fully understood. Therefore, further investigation into the role of macrophage PANoptosis in duodenal microinflammation and its impact on the progression of FD could improve the understanding of the pathogenesis of FD and provide a theoretical foundation for the development of more effective clinical treatments.