Goblet cells (GCs) are distributed across various organs, including the digestive tract, respiratory tract, and conjunctiva. Despite their distinct functions arising from evolutionary adaptations, GCs have common functions (1). Mucus and mucin produced by GCs and enterocytes are crucial components of the first line of defence, interacting with the immune system to maintain homeostasis (2). However, under pathological conditions, this interaction can result in various disease phenotypes. The two most prevalent diseases of the nasal mucosa are allergic rhinitis (AR) and chronic rhinosinusitis, both of which share common characteristics, including increased mucin 5AC (MUC5AC) and MUC5B secretion. Airway secretions originate primarily from GCs, glandular tissues, and vascular exudates (3). The current treatments for AR, including antihistamines, leukotriene antagonists, allergen immunotherapy, and biologics, primarily target traditional immunological pathways (4). In contrast, chronic rhinosinusitis management relies on pharmacological and surgical interventions, focusing less on the role of GCs. Therefore, a comprehensive investigation of GC function in different diseases and the composition of nasal secretions may reveal the fundamental mechanisms underlying these different hypersecretions.

Neuro-immunity encompasses the bidirectional communication pathways between the nervous and immune systems, vital for maintaining tissue homeostasis, combating infections, and modulating inflammatory responses (5). Neural sensitisation significantly increases acetylcholine release, enhancing GC secretion. Meanwhile, neuromedin U mediates eosinophil activation and increases the number of intestinal GCs, potentially impacting mucus secretion due to eosinophilic effects (6). Moreover, neuron–GC signalling via the calcitonin gene-related peptide (CGRP)–receptor active modification protein-1(RAMP1) axis protects against colitis (7).

In the airways, neural endings facilitate GC degranulation through various neuroimmune mechanisms, including those mediated by neuropeptides, neurotransmitters, and transient receptor potential (TRP) channels (8). As recently reported, current medications often prove insufficient for patients with AR exposed to physicochemical stimuli. Neuroimmune modulation of GCs likely contributes to this challenge. A deeper understanding of the neuroimmune mechanisms underlying GC metaplasia and degranulation in AR may provide valuable insights into novel therapeutic strategies for managing this condition.

The neuroimmune system is pivotal in the GC hypersecretion associated with AR. Although our understanding of the effects of GCs on AR remains limited, research on other systems provides valuable information. For example, voltage-gated sodium channel 1.8+ neurons are present near mucus-secreting GCs, where intestinal nerve–GC signalling may induce mucus secretion via the CGRP–RAMP1 axis (7). Additionally, intestinal neuronal cells release interleukin (IL)-18, which promotes mucin secretion (9). The specific mechanisms in the intestine are shown in Figure 1A . Mucosal barrier immunity is essential for maintaining the commensal microflora and combating infection by invasive bacteria, whereas tuft cell-derived acetylcholine regulates epithelial mucus secretion (10). Moreover, inhibiting TRP cation channel subfamily M member 4 (TRPM4) protein activity in cystic fibrosis cell lines abolished MUC5AC secretion (11). Finally, nerve–GC interactions promote allergic conjunctivitis through goblet cell-associated antigen passages (GAPs). The function of GAP as a novel therapeutic target for airway allergic inflammation warrants further investigation.

In asthma, substance P produced by airway sensory neurons amplifies allergy-induced GC hyperplasia and MUC5AC hypersecretion (12). Similarly, activating the gamma-aminobutyric acid (GABA) type A receptor, a specific chloride channel, triggers mucin release. GABA secreted by neuroendocrine cells also promotes GC hyperplasia, resulting from the increased trans-differentiation of ciliated airway epithelial cells and club cells into mucin-producing GCs following ovalbumin challenge. GCs are often located near airway sensory neuron terminals and express receptors for various neuropeptides, including muscarinic acetylcholine receptor type 3 (M3), neurokinin-1 receptor, GABA type A receptor, and vasoactive intestinal peptide (VIP) receptor 1 (13). TRP melastatin subtype 8 (TRPM8), a calcium channel, modulates intracellular calcium levels and influences GC activity, leading to MUC5AC secretion, particularly during cold exposure (14). The specific details are illustrated in Figure 2A and Table 1 .

The airways involve three neural pathways, namely sympathetic (adrenergic), parasympathetic (cholinergic), and non-adrenergic non-cholinergic (NANC) (31). GC degranulation is primarily regulated by the cholinergic and NANC sensory nervous systems (32). In the nasal mucosa, NANC nerve fibres are predominantly found in the trigeminal nerve’s C fibres, which are particularly susceptible to direct activation by allergic mediators (31). Afferent C fibres often express TRP ion channels, which promote mucin synthesis and secretion by releasing neuropeptides and neurotransmitters (12).

Dupilumab, a monoclonal antibody targeting IL-13Ra and IL-4Ra in clinical trials, inhibits GC metaplasia and excessive mucus secretion (47). The heat-shock protein 90 inhibitor geldanamycin reverses IL-13-induced airway GC metaplasia and improves airway remodelling (48). In human airway epithelial cells, the anticholinergic agent tiotropium attenuates IL-13-induced GC metaplasia (49). Additionally, tiotropium suppresses TRPV1 neuronal activity independently of M3 receptor blockade (49). TRPV1 agonists such as capsaicin can treat atopic rhinitis by leveraging the principle that the nasal mucosa enters a refractory period after stimulation; however, they have not significantly improved outcomes for patients with identified allergens (50). Furthermore, neuropeptides secreted by the sensory nerves and neuroendocrine cells, such as CGRP, Substance P, and GABA, can induce GC degranulation (12, 31, 51). Therefore, targeting neurotransmitter receptors in GCs is a promising therapeutic strategy. For example, stapled peptides can disrupt Ca²⁺ signalling and reduce stimulated mucin secretion (52). Although not yet explored in AR, stapled peptides represent an ‘ideal’ strategy for disrupting Ca²⁺ signalling and reducing mucin secretion.

In addition to targeting inflammatory mediators and signalling pathways, treatment methods should aim to reverse persistent GC metaplasia. This approach includes epigenetic editing to silence genes such as SPDEF. MicroRNAs, such as miR-141, miR-205-5p, miR-92a, and circZNF652, also target MUC5AC to alleviate mucus hypersecretion caused by allergic airway inflammation and reduce the nasal mucosal epithelial remodelling (21, 22, 53). Blocking GC metaplasia is crucial for promoting mucosal barrier restoration (23). The specific targets are listed in Table 2 .

The neuroimmune regulatory mechanisms of GCs in other systems, such as the lower airways and intestines, have been extensively studied, including pharmacological interventions. However, the upper airways have not received adequate attention. Developing nasal sprays for delivering therapeutic agents, such as exosomes or capsaicin, or targeting genes in the nasal mucosa could be beneficial. For instance, mesenchymal stem cells overexpressing IL−10 significantly reduce the number of GCs in an allergic airway inflammation model (55). Additionally, GCs are poorly studied outside of their secretory role, and their associations with various diseases suggest the need to explore these extra functions further (56). The potential role of GCs in immune surveillance suggests that they could serve as new targets for treating allergic diseases.

The role of nerve–GC signalling requires consideration in airway allergic diseases. Increased nasal secretion in AR is closely associated with GC metaplasia and degranulation, orchestrated by a complex network of cytokines, neurotransmitters, neuropeptides, and their respective receptors, including TRP channels. However, the precise functional mechanisms remain unclear. Zhao (57) developed and validated a chemical approach to induce high-purity GCs. Their use in functional experiments on neuropeptides and their receptors will help elucidate specific signalling pathways. In addition, introducing a hydrocarbon-stapled peptide conjugated with cell-penetrating peptides into cultured human airway epithelial cells can inhibit stimulated secretion without affecting basal secretion (54). Further breakthroughs in AR could provide multidimensional approaches for treating mucus hypersecretion diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis.

Although the functions of GCs in the gut, conjunctiva, and airways are distinct under pathological conditions, they all imprint the central nervous system, which regulates peripheral diseases (58). For instance, similar to the storage of immune memory in the insular cortex following dextran sodium sulphate-induced colitis, DBH⁺ neurons in the solitary tract nucleus modulate airway hyperresponsiveness in asthma (59, 60). However, phenotypic changes in peripheral neurons during airway inflammation and their impact on GC function remain largely unknown. Thus, we introduced the nose–brain axis (61), building on pioneering research in related fields. Adaptations of the central nervous system in AR and their effects on GC metaplasia and degranulation are not fully understood. Shifting the research focus from peripheral to central mechanisms offers a transformative perspective on AR pathogenesis.

GCs are not merely mucus barriers but also immune barriers, acting as the first line of defence against airway mucosal immunity. Previous research has been limited to the immunological aspects; however, future basic and clinical studies should focus on the neuroimmunological regulation of GCs. Current treatments for airway hypersecretion primarily target immune factors such as IL-13. More in-depth research on GCs is urgently needed, and new treatment strategies specifically targeting GCs are essential.