Inflammation is a fundamental driver in the progression of gastric precancerous lesions, with its pathological influence extending throughout IM and the Correa cascade (2). During the initial stages of the disease, autophagy exerts cell-autonomous (an intrinsic and proactive self-protective response mounted by the epithelial cell itself upon initial exposure to inflammatory stimuli) anti-inflammatory effects by eliminating intracellular pathogens, damage-associated molecular patterns released from damaged organelles and misfolded protein aggregates, sources of inflammatory signals, thereby effectively inhibiting the activation of pro-inflammatory signaling pathways, including the NLRP3 inflammasome (Fig. 1A) (36,37). Conversely, when autophagy is impaired or structurally defective, this protective mechanism is disrupted, leading to abnormal activation and persistence of inflammatory responses. Dysfunction of the autophagy-lysosome pathway may constitute a common pathological basis for inflammatory diseases (38). The transcription factors TFEB and TFE3, as primary regulators of macroautophagy/autophagy and lysosomal function, may act as key molecular hubs linking these pathological processes (39).

Prolonged inflammatory stimulation leads to impaired autophagic flux, resulting in excessive activation of the NLRP3 inflammasome and facilitating the formation and oligomerization of inflammasome complexes (40,41). These complexes include nucleotide-binding oligomerization domain-like receptors, adaptor proteins and pro-caspase-1 (42). The activation of these inflammasome complexes causes the proteolytic cleavage of the zymogen pro-caspase-1 into its enzymatically active form and catalyzes the maturation and release of pro-inflammatory cytokines IL-1β and IL-18 (43,44). However, when autophagic activity exceeds physiological thresholds, its compensatory enhancement may lead to a pathological state of excessive autophagy. Excessive degradation of organelles may precipitate an energy metabolic crisis, activating the NF-κB signaling pathway through the AMPK/mTOR pathway and initiating a cascade of inflammatory responses (45,46). Moreover, the impaired autophagic flux enhances the activation of the TLR4/MyD88, MAPK and downstream NF-κB signaling pathways and exacerbates the release of pro-inflammatory factors (IL-6, IL-1β, tumor necrosis factor-α and IL-8) and other factors, including chemokines CCL7 and CXCL16 (47–49). Notably, IL-8 can enhance autophagy and cell invasiveness by regulating the phosphorylation of the PI3K/AKT pathway. Elevated levels of IL-8 are associated with a marked increase in the expression of autophagic markers LC3II, ATG5, ATG7, the apoptotic factor Beclin1 and the ATG12-ATG5 complex (50). Furthermore, NF-κB initiates the activation of the NLRP3 inflammasome by upregulating pro-IL-1β and NLRP3 expression, thereby establishing a pro-carcinogenic feedback loop (Fig. 1B) (51).

Autophagy is a key mechanism by which cells manage endogenous and exogenous stress, thereby enhancing innate and adaptive immunity. Autophagy enhances innate pathogen detection, antigen presentation, pathogen clearance and lymphocyte expansion (52,53). In the context of innate immunity, autophagy serves as the primary defense mechanism against microbial invaders. Upon detecting invading bacterial pathogens and their associated infection signals, autophagic proteins serve as cytosolic sensors, promptly activating the autophagy pathway and initiating protective mechanisms for the host (54). When the gastric mucosa is invaded by pathogens such as H. pylori, the autophagy system can promptly detect the specific infection signals of bacteria, rapidly activate autophagy-associated proteins as intracellular recognition receptors and initiate the autophagy pathway to encapsulate and degrade bacteria, thereby limiting the proliferation of pathogens and mitigating damage to the gastric mucosa (55). During innate immune responses, autophagy facilitates the presentation of degradation products through the lysosomal pathway to major histocompatibility complex (MHC) class II molecules (56). This stimulates and refines the self-tolerance of the CD4⁺ T cell repertoire, enhances CD4⁺ T cell responses to pathogens and tumors and facilitates the clonal expansion of B and T cells, thereby strengthening overall immune function (Fig. 2A) (57). Conversely, autophagy is key in distinguishing self from non-self by regulating exogenous factors in antigen-presenting cells, such as MHC-antigen complexes, and endogenous factors in T cells, including cell signaling, survival, cytokine production and metabolism. This renders it a target for regulating T cell immunity (58). Furthermore, the autophagy-associated protein phosphatidylinositol 3-kinase catalytic subunit type 3/vacuolar protein sorting 34 directly affects T cell function by maintaining metabolic homeostasis (59). However, a deficiency in autophagy leads to abnormal activation of mTORC1 and c-Myc signaling pathways, which enhances glycolytic metabolism and impairs the function of regulatory T cells (Tregs) (60). Deficient Treg function may result in uncontrolled inflammatory responses. This increases the risk of peptic ulcers in H. pylori infection and drives the pathological remodeling of the gastric mucosa from chronic inflammation to atrophy and IM (61). The gastric mucosal microenvironment relies on autophagy-mediated antigen presentation, T cell repertoire shaping and the maintenance of Treg function (62).

Following H. pylori infection, these autophagy-dependent immune regulations are locally activated or dysregulated in the gastric mucosal microenvironment, influencing the establishment of protective tolerance or the progression toward chronic inflammation and carcinogenesis (62,63). This mechanism involves the modification of surface molecules and the regulation of macrophage and T cell functions to evade immune surveillance (64). H. pylori transforms autophagy into a pro-survival pathway by inhibiting autophagosome-lysosome clearance, which serves as a key strategy for persistent infection (65). At the immune response level, H. pylori components directly enhance the secretion of IFN-γ and IL-12 and simultaneously inhibit IL-2 production and the cell proliferation necessary for Th2 responses, thereby promoting Th1 polarization (61,66). This polarization state exacerbates local inflammatory damage to the gastric mucosa, induces abnormal apoptosis and repair of epithelial cells and can promote the transformation of normal gastric mucosa to IM in the long term (67). Although traditional views highlight Th1 immunity in gastritis and IM, emerging evidence indicates that the interaction network of Th2-associated cytokines (IL-33 and IL-13) with M2 macrophages, mast cells and eosinophils is an important trigger for tumorigenesis (68). This network can disrupt the integrity of the gastric mucosal barrier, thus accelerating disease progression (68). H. pylori can induce the strong activation and maturation of human immature dendritic cells (Fig. 2B) (69). However, continuous antigen exposure may induce functional exhaustion of dendritic cells, which affects the effective establishment of a Th1 immune response, resulting in insufficient immune clearance and persistent chronic inflammation (70). This promotes the occurrence of IM in the gastric mucosa during repeated injury and abnormal repair.

Autophagy, a highly conserved intracellular degradation mechanism, is key in various biological processes, including cell survival, death, differentiation and metabolism (71). Under normal physiological conditions, the gastric mucosa is primarily composed of gastric-type epithelial cells. Similar to most normal cells, autophagy facilitates self-renewal and differentiation by degrading excessive cell proteins and organelles, thus providing metabolic precursors and energy (Fig. 3A) (72). Autophagy serves a protective function by attenuating damage from external stimuli. For example, it protects gastric mucosal epithelial cells against ethanol-induced apoptosis and mucosal damage by inhibiting the generation of ethanol-induced reactive oxygen species, preserving antioxidant enzyme integrity and reducing lipid peroxidation (73). Additionally, signaling proteins such as IFN-γ decrease epithelial cell apoptosis by inducing autophagy and simultaneously suppressing the aberrant proliferation of gastric progenitor cells. This dual action helps maintain a balance between infection defense and carcinogenesis suppression within the gastric mucosa (74).

Chronic pathological stimulation causes secretory columnar epithelial cells (which produce gastric acid and mucus) to lose their inherent functional characteristics and differentiate into goblet cells, intestinal-type absorptive cells with microvilli and Paneth cells (75–77). This cellular remodeling necessitates enhanced degradative capacity to facilitate structural transformation (72). However, autophagy dysregulation leads to dual pathological effects. Specifically, impaired or excessively enhanced autophagic flux loses its protective effect on gastric epithelial cells and accelerates their death (78); it also disrupts the degradation-remodeling balance and weakens the normal support for cell transdifferentiation. This functional imbalance provides a pathological basis for aberrant cell transformation in IM (Fig. 3B). Inflammatory factors can trigger the deconstruction of the chief cell secretory apparatus and transcriptomic reprogramming, a process dependent on autophagy and coordinated changes in gene transcription (79,80). In the gastric mucosa, autophagy dysregulation may affect stem cell differentiation pathways, resulting in aberrant cell phenotypes and functions (81,82). In the absence of autophagy, gastric mucosal stem cells demonstrate a bias toward intestinal differentiation (83). At the molecular level, crosstalk between autophagy and signaling pathways is key for stem cell differentiation, such as influencing differentiation direction via regulation of the Wnt pathway (84) and modulating cell metabolic status and differentiation capacity through interaction with the mTOR signaling pathway (85,86). Dysregulation of these pathways in the gastric mucosa may lead to abnormal stem cell differentiation, promoting IM development (87).

The protective and pathogenic effects of autophagy on gastric mucosa, based on the evidence from inflammation, immune regulation and cell differentiation, are not absolute but depend on a molecular switch influenced by multiple threshold factors (62). At basal levels of autophagic activity, autophagy inhibits the overactivation of the NLRP3 inflammasome and NF-κB pathway by clearing pathogens, damaged organelles and misfolded proteins, thereby exerting anti-inflammatory and homeostatic functions (88,89). However, prolonged suppression or compensatory overactivation of autophagy may shift its role from protective to pathogenic (62). Specifically, the key threshold factors include the bidirectional threshold effect of oxidative stress. Low-level oxidative stress is eliminated through autophagy, thereby exerting protective effects, whereas high-level stress that exceeds autophagic capacity may result in autophagy blockage or hyper-activation, leading to organelle degradation, energy metabolism crisis, NF-κB activation and promotion of epithelial cell apoptosis and transdifferentiation (90–92). Elevated IL-8 enhances autophagic activity and cellular invasiveness through PI3K/AKT pathway activation, thereby establishing a positive-feedback loop (50). Appropriate levels of cytokines, particularly IFN-γ, in the immune microenvironment induce protective autophagy, whereas continuous abnormal elevation may disrupt immune tolerance by promoting Th1 polarization and impairing Treg function (75). Collectively, these factors determine the transition of autophagy from a protective barrier to a driver of IM.