Acute pancreatitis is an inflammatory disease of the pancreatic exocrine glands associated with tissue damage and necrosis (1). The core pathophysiology of this disease involves abnormal trypsin activation, leading to autodigestion of acinar cells, which subsequently triggers amplification of a cascade of localized inflammatory responses. In severe cases, it can progress to systemic inflammatory response syndrome (SIRS) and multi-organ failure (2). Common clinical factors contributing to the disease include biliary system disorders (such as cholelithiasis), alcoholism, traumatic injury, drug toxicity, and autoimmune disorders ( Table 1 ).

Acute pancreatitis, one of the gastrointestinal diseases with the highest hospitalization rates globally, is characterized by sudden severe abdominal pain accompanied by multi-organ dysfunction. It carries the potential risk of progressing to pancreatic necrosis and persistent organ failure, exhibiting an unpredictable and potentially fatal course (9). Based on the Revised Atlanta Classification (RAC), the severity of AP can be categorized into three levels: mild acute pancreatitis, moderately severe acute pancreatitis, and severe (SAP). This classification is determined by factors such as the duration of organ failure (transient/persistent) and the presence of local or systemic complications (10). From a cellular mechanism perspective, the functional homeostasis of pancreatic acinar cells (PAC) relies on the precise coordination of organelles like the endoplasmic reticulum, mitochondria, and lysosomes. Dysfunction in these organelles can disrupt the metabolic balance within PACs, triggering the pathological process of pancreatitis and leading to cell death. Although approximately 80% of acute pancreatitis (AP) cases exhibit a self-limiting course, 20% of patients still progress to moderately severe acute pancreatitis or severe acute pancreatitis (SAP), complicated by systemic inflammatory response syndrome (SIRS) and multi-organ failure, with a mortality rate as high as 39% (11). Survivors frequently suffer from severe short-term complications and long-term organ damage. Currently, there are no internationally approved specific drugs for acute pancreatitis and its complications. Existing treatments primarily involve intravenous fluid resuscitation, analgesia, enteral nutrition, protease inhibitors, and other combination therapies. Intensive care, organ support, parenteral nutrition, antibiotics, and pancreatic exocrine and endocrine replacement therapies may be necessary in severe cases (12). Unfortunately, these treatments, due to their lack of specificity, often have limited efficacy and may be associated with adverse reactions, resulting in poor patient outcomes (13). Hence, the development of novel diagnostic and therapeutic approaches has become an urgent need in current research.

Recent research has focused on the mechanism of autophagy regulation in AP. As a core catabolic pathway for maintaining cellular homeostasis, autophagy exerts a protective effect on pancreatic cells by eliminating damaged organelles (14). Genetic studies have confirmed that defects in genes encoding autophagy-related proteins (such as ATG5 and ATG7) or lysosome function-related proteins (such as LAMP2) can disrupt the autophagic flux in acinar cells, thereby inducing pancreatitis (15). It is noteworthy that in the mammalian target of rapamycin (mTOR) signaling pathway, the PI3K/AKT/mTOR axis plays a pivotal role, particularly mTOR complex 1 (mTORC1), which regulates the initiation of autophagy in acute pancreatitis (AP) through ULK1 phosphorylation (16). Dysregulation of this signaling axis promotes trypsinogen activation, thereby triggering an inflammatory cascade (17). The dynamic regulatory mechanism of autophagy activity exerts crucial protective effects on the pancreas, providing novel therapeutic targets for AP.

In the autophagy regulatory network, microRNAs (miRNAs) represent a class of small, evolutionarily conserved non-coding RNA molecules that mediate post-transcriptional gene silencing by binding to the 3’ untranslated region (UTR) of target mRNAs. They are widely involved in cellular processes such as development, differentiation, and apoptosis (18). Research indicates that miRNAs participate in almost every stage of autophagy, including critical steps like phagophore formation, autophagosome maturation, and lysosomal degradation (19). Meanwhile, MSCs therapy exhibits unique advantages in the treatment of AP due to its multipotent differentiation capacity and paracrine characteristics (20). MSCs not only directly repair and replace damaged tissues (21) but also secrete anti-inflammatory factors to inhibit apoptosis and fibrosis (22). The exosomes secreted by MSCs, with their low immunogenicity, long-lasting circulation, and ability to penetrate the blood-brain barrier, serve as ideal drug delivery vehicles (23). These nanovesicles efficiently carry miRNAs, proteins, and immunomodulatory factors, providing a technical platform for targeted modulation of the PI3K/AKT/mTOR pathway. Based on these breakthroughs, this article systematically elucidates the molecular mechanism of exosome-delivered miRNA in regulating the PI3K/AKT/mTOR pathway in AP, aiming to provide an innovative theoretical framework and transformation strategy for precise disease diagnosis and treatment Figure 1 .

Acute pancreatitis is a disease characterized by acute inflammation of the pancreatic parenchyma, which in severe cases can lead to local tissue destruction and multiple organ dysfunction (24). Its pathophysiology exhibits a multidimensional interaction, involving crucial pathological processes such as abnormal activation of trypsinogen, inflammatory cascade reactions, metabolic imbalances, and cell death. These factors collectively contribute to pancreatic tissue damage and dysfunction.

Abnormal autophagy in acinar cells during AP is closely associated with various signaling pathways ( Table 2 ), such as the AMPK/SIRT1 signaling pathway (61, 69), the PI3K/AKT/mTOR signaling pathway (17), the AKT/AMPK/mTOR signaling pathway (70), the Beclin-1 signaling pathway (71), the JAK/STAT3 signaling pathway (72), and the NF-kB/TNFα/SIRT1 signaling pathway (73). Protein kinase B (AKT) is downstream of phosphatidylinositol 3-kinase (PI3K) and plays an antagonistic role in autophagy, involving the activation of the mTORC1 complex and the inhibition of ULK1 and ATG13 to block the initiation of autophagy (74). Mammalian target of rapamycin (mTOR), as a “metabolic sensor,” blocks autophagy by inhibiting the ULK1 complex when cellular energy is sufficient, serving as a key negative regulator of autophagy (75). Among these, the regulatory roles of PI3K/AKT and mTOR have been widely recognized and are considered key molecules in autophagy (76). Therefore, we will focus on the effects of PI3K/AKT/mTOR on AP in the following discussion.

The PI3K/AKT/mTOR signaling pathway plays a pivotal role in regulating inflammatory responses and autophagy. Studies have indicated that both inhibition and activation of this pathway can improve the pathological process of AP, but the therapeutic efficacy depends on the spatiotemporal specificity of the target and regulatory mechanism. Multiple studies have demonstrated that inhibiting the PI3K/AKT/mTOR signaling pathway can activate autophagy, suppress trypsinogen activation, reduce tissue damage, and hinder inflammatory progression, thereby improving AP. For instance, research has found that phillygenin (PHI) and xanthohumol can restore impaired autophagic flux by inhibiting the PI3K/AKT/mTOR signaling pathway, reducing p62 levels, and increasing LAMP-2 levels, ultimately improving AP and preventing the progression and deterioration of SAP (17, 47). Yang et al. discovered that Chaiqin Chengqi Decoction (CQCQD) attenuates the severity of alcohol-induced AP by activating the antioxidant protein response and downregulating the PI3K/Akt signaling pathway in the pancreas and visceral adipose tissue (77). Wortmannin significantly reduces the redistribution of CTSB by inhibiting PI3K, effectively preventing intrapancreatic activation of trypsinogen in vivo (78). PI3K/Akt inhibitors also lower the expression of inflammatory cytokines in SAP rats, exerting potent anti-inflammatory and antioxidant effects by inhibiting NF-kB nuclear translocation and downregulating the transcription of NF-kB-dependent pro-inflammatory genes, including TNF-α, IL-1β, and IL-6 (77, 79–82).

However, another set of studies indicates that activating the PI3K/AKT/mTOR signaling pathway under specific conditions to inhibit autophagy can also play a role in improving AP. Macrophages are the most abundant immune cells in the regenerating pancreas (83). The regeneration process of exocrine acinar cells involves a transient phase of inflammation, acinar-to-ductal metaplasia (ADM), and acinar redifferentiation (84). Activation of PI3K-AKT in macrophages promotes inflammation resolution during the ADM phase, improving pancreatic regeneration and organ function recovery (85, 86). Studies have found that IGF-1 (insulin-like growth factor, a PI3K agonist), MZB1 (marginal zone B and B-1 cell-specific protein 1), and rhubarb inhibit autophagy by activating the PI3K/AKT/mTOR signaling pathway, stimulate pancreatic cell proliferation, induce acinar ADM and redifferentiation, and accelerate pancreatic repair (87–89). It’s worth noting that IGF-1 can also significantly reduce the expression of proinflammatory cytokines such as IL-6 in a dose-dependent manner, exhibiting the same anti-inflammatory effect as the PI3K inhibitor wortmannin. Li et al. (90) found that ulinastatin has anti-inflammatory and antioxidant functions in LPS (lipopolysaccharide)-treated RAW264.7 cells, and its protective effect can be attributed to the activation of the PI3K/Akt-Nrf2 axis and the inhibition of the Thr183p/JNK/NF-κB axis. Wang et al. (91) found that LXA4 (lipoxin A4) activates the PI3K/Akt and PKC pathways, induces Nrf2 phosphorylation, leads to the upregulation of HO-1, reduces cell adhesion, and protects mitochondrial function, exerting a cytoprotective effect in lung injury caused by SAP. Research shows that spautin-A41, as a novel and effective autophagy inhibitor, appears to have a therapeutic effect on AP, and its mechanism may be to reduce the expression level of the PI3K complex, thereby inhibiting acinar trypsin activation and inflammatory response (92).

Indeed, numerous studies have established a close relationship between AKT-regulated autophagy and inflammatory responses. Autophagy can negatively regulate inflammatory reactions by eliminating damaged mitochondria and aggregated inflammatory signaling proteins, thereby reducing the production of reactive oxygen species (ROS) (93). In fact, inflammation and autophagy are mutually causal, and a chronic inflammatory environment can also lead to impaired autophagy function (94). Various studies have demonstrated that inflammatory factors can inhibit ATG gene expression and disrupt autophagosome-lysosome fusion through the activation of the NF-κB pathway, ultimately suppressing autophagy (95). Therefore, during the acute phase of AP, the PI3K/AKT/mTOR signaling pathway can be inhibited to activate autophagy, clear damaged organelles, and suppress trypsin activation. Conversely, during the recovery phase, activating this pathway promotes acinar regeneration and inflammation resolution.

MSCs are a type of adult stem cell characterized by their low immunogenicity and multilineage differentiation potential. These cells have demonstrated significant efficacy in the treatment of various diseases, including osteoarthritis (110), liver fibrosis (111), and myocardial infarction (112). In the context of AP, early studies have confirmed that human bone marrow-derived MSCs (BMSCs) can alleviate pancreatic damage in a rat model of AP by suppressing inflammatory responses (113). Subsequent research has further untangled the underlying mechanisms by which BMSCs improve SAP, including reducing oxidative stress (114), promoting angiogenesis (115), and inhibiting pancreatic necrosis (116). Recent studies have untangled that exosomes serve as pivotal mediators of intercellular communication and therapeutic effects. Exosomes exhibit high bioavailability, stability, and the capacity to traverse biological barriers, enabling them to deliver functional molecules (e.g., miRNAs) to distal target cells, regulate gene expression, and enhance tissue healing (117). Consequently, exosomes represent an ideal platform for miRNA delivery, effectively overcoming the challenges of low delivery efficiency and rapid degradation associated with free miRNA therapeutics. Mesenchymal stem cells (MSCs) constitute one of the primary sources of exosomes. The MSC-derived exosomes carry specific miRNAs that exert therapeutic effects by modulating key signaling pathways. For instance, Song et al. (118) demonstrated that BMSCs significantly reduce pancreatic damage in SAP by upregulating the PI3K/AKT/MTOR pathway and inhibiting the expression of autophagy key molecules Beclin-1 and LC3. Further research from the same team (119) showed that inhibiting miR-138-5p in MSCs activates the FAK/PDK1/AKT/mTOR pathway, suppressing autophagy in SAP. Additionally, knocking down miR-141-3p in MSCs promotes pancreatic cell proliferation by upregulating the expression of β-catenin, c-Myc, and cyclin D1. Song et al. (120) found that miR-29a-3p carried by MSC-derived exosomes alleviates myocardial damage in a SAP model by inhibiting the HMGB1/TLR4/AKT axis. Moreover, miR-216a-5p from MSC-derived exosomes induces the transition of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype by inhibiting the TLR4/NF-κB signal and activating the PI3K/AKT pathway, thereby reducing systemic inflammation (121). A recent study (122) revealed that MSC-derived exosomes maintain mitochondrial dynamics stability and enhance autophagy by delivering miR-214-3p to inhibit the PI3K/AKT/mTOR pathway, thus alleviating inflammatory responses in ulcerative colitis. This mechanism may have potential applications in the treatment of AP.

More importantly, the potential of exosomes as miRNA delivery vehicles is not limited to MSCs. A variety of cell types, including immune cells, endothelial cells, epithelial cells, and even tumor cells, can secrete exosomes carrying distinct miRNA profiles, which may similarly influence the progression of AP through analogous mechanisms (123, 124). These exosomes also exhibit favorable characteristics, such as stability, low immunogenicity, and targeted delivery potential (125), thereby expanding the therapeutic possibilities for sEV-based AP treatment strategies.

In summary, exosomes, particularly those derived from therapeutic cells such as MSCs, exert multifaceted therapeutic effects—including anti-inflammatory, anti-autophagic, and pro-regenerative activities—by delivering miRNAs to modulate key signaling pathways such as PI3K/AKT/mTOR and TLR4/NF-κB. This “cell-exosome-miRNA” cascade regulation model provides a new approach for precision treatment of AP. However, further research is needed to validate the standardized preparation of exosomes (regardless of their source), miRNA delivery efficiency, and long-term safety for clinical translation, as current related studies are limited.

In recent years, the risk factors for acute pancreatitis have gradually increased, leading to a rise in its incidence and mortality rates. This trend is particularly concerning for severe acute pancreatitis, where conventional diagnosis and treatment often fail to prevent serious complications and recurrences. Therefore, there is an urgent need for innovative optimizations in early diagnosis, prognosis evaluation, and therapeutic approaches. The pathological progression of AP involves a complex interactive network of autophagic imbalance, uncontrolled inflammation, and impaired cell repair. This study systematically elucidates the central role of impaired autophagic flux in AP, untangles the causal relationship between lysosomal dysfunction (such as LAMP degradation and imbalance of cathepsin activity) and abnormal activation of pancreatic enzymes, and proposes that “autophagy activation with delayed flux” is a key feature of acinar cell injury in AP. This finding is consistent with previous research indicating that the accumulation of vacuoles resulting from autophagosome-lysosome fusion impairment is a common phenomenon in various experimental AP models.

The bidirectional regulatory characteristics of the PI3K/AKT/mTOR pathway are a critical aspect to consider in AP treatment. Our study reveals that this pathway may exhibit opposing effects at different stages of AP: during the acute phase, inhibiting the pathway can activate autophagy and reduce pancreatic enzyme activation, while activating the pathway during the repair phase promotes acinar regeneration and inflammation resolution. This suggests that interventions targeting PI3K/AKT/mTOR require dynamic regulation based on the disease phase. For instance, early use of wortmannin to inhibit PI3K can block abnormal activation of pancreatic enzymes mediated by CTSB, while later activation of the pathway through IGF-1 may accelerate tissue repair. This phase-dependent therapeutic strategy offers new insights for optimizing clinical medication regimens. Future research could further develop smart responsive delivery systems (such as pH-sensitive exosomes) to release PI3K inhibitors (like wortmannin) in the acidic microenvironment of the acute phase and IGF-1 activators during the repair phase.

With the extensive research on miRNAs, we have discovered that miRNA regulatory networks exhibit significant bidirectional plasticity in AP. Pro-inflammatory miRNAs (such as miR-155 and miR-216a) exacerbate autophagic imbalance by activating PI3K/AKT/mTOR or inhibiting PTEN, while anti-inflammatory miRNAs (like miR-148a and miR-20b-5p) alleviate inflammatory damage by inhibiting NF-κB/STAT3 signaling. Notably, molecules like miR-141 can both inhibit autophagosome formation (via the HMGB1/Beclin-1 axis) and reduce inflammatory responses, making them promising candidates for AP gene therapy due to their multi-target characteristics. However, organ-specific delivery and off-target effects of miRNAs remain major obstacles for clinical application.

MSCs and their exosomes demonstrate significant advantages in AP treatment due to their unique “multi-target synergistic regulation” properties. They can simultaneously target autophagy, inflammation, and regeneration pathways by delivering functional miRNAs. For example, miR-29a-3p carried by exosomes can inhibit the HMGB1/TLR4/AKT axis to reduce myocardial injury, while miR-216a-5p induces macrophage phenotype transformation through the TLR4/NF-κB and PI3K/AKT pathways, alleviating systemic inflammatory responses. This “cell-exosome-miRNA” cascade model overcomes the limitations of single-target interventions. Nevertheless, current research on the relationship between miRNAs and AP progression is still in its infancy, and studies examining the relationships between miRNAs, autophagy, and organelles in AP are scarce. Therefore, more systematic and in-depth investigations are needed to explore these relationships.

In conclusion, the therapeutic strategy for AP is shifting from single anti-inflammatory approaches to multi-target synergistic interventions. By integrating the restoration of autophagic homeostasis, inhibition of inflammatory pathways, and promotion of cell regeneration, precision and personalized treatment for AP may be achieved in the future. To achieve this goal, clinical translation can be advanced in stages. In Phase I trials, the pharmacokinetics and safety of exosomes are evaluated. In Phase II trials, relevant biomarkers are screened based on the subtypes of AP (such as biliary-derived and hyperlipidemia-induced). In Phase III trials, a multicenter study is conducted in combination with protease inhibitors to verify the efficacy of the trifecta therapy of “anti-inflammation - autophagy repair - regeneration”. This process not only provides a clear direction for AP research but also offers a reference and insight for interdisciplinary treatment strategies for other autophagy-related diseases.