Search Results (335)

The development of new methods enhancing the growth and yield of cereals is still needed in crop production due to their great importance in human diet and as livestock fodder. In our study, new fertilizer-biostimulators with micro- and macroelements and extract containing lipochitooligosaccharides (LCOs) produced by Rhizobium leguminosarum bv. trifolii were used for stimulation of growth of barley and triticale in greenhouse conditions. The preparations were applied at the tillering and shooting stages, whereas plant traits were studied at flowering and at full maturity. The best results were recorded after the joint treatment of the plants with LCOs and mineral fertilization. The application of such a mixture significantly increased the length and mass of roots at flowering in both studied species. A beneficial effect of the treatment was also observed in barley and triticale yields. At full maturity, the grain mass per plant was significantly enhanced, which was the effect of an increased number of grains per ear and increased mass of 1000 grains. Full article

Ducks, once considered mere reservoirs, now serve as both victims and amplifiers of persistent highly pathogenic avian influenza (HPAI) virus cycles in wild populations. The molecular pathogenesis of HPAI is shaped by complex, dysregulated molecular networks, necessitating a systems biology approach that integrates computational modeling of host–pathogen interactions. Despite recent advances, a comprehensive understanding of the signaling pathways, molecular mechanisms, and hub genes driving HPAI H5N1 pathogenesis in avian hosts remains incomplete. This study addresses this gap by employing an integrated multi-omics strategy—combining transcriptomic, proteomic, and phosphoproteomic analyses—to map the signaling networks and key host factors involved in HPAI H5N1 infection in duck lung tissue. Our network analysis revealed activation of RIG-I-like receptor, toll-like receptor, NOD-like receptor, NF-κB, and JAK/STAT signaling pathways. Phosphoproteomic profiling independently confirmed the activation of these pathways, supporting the integrated network findings. Key regulatory hub genes identified include STAT1, DDX58 (RIG-I), MYD88, NFKBIA, NFKB1, IRF7, SOCS3, ACTB, TLR4, TLR7, IL-6, CASP1, and CASP8, which form a central hub in duck antiviral immunity. Some of these genes may represent promising targets for therapeutic or vaccine development against avian influenza. Collectively, this work delineates the critical signaling pathways and hub genes underlying HPAI H5N1 pathogenesis in ducks through comprehensive multi-omics integration. Full article

Ischemia and reperfusion (IR) injuries may produce deleterious effects on hepatic tissue after liver surgery and transplantation. The consequences of IR are more evident in pathological steatotic livers. Spirulina (Arthrospira platensis) is known for its potential to modulate inflammatory responses and enhance antioxidant defenses. The current investigation assessed whether spirulina pretreatment mitigates hepatic IR injury exacerbated by steatosis in rats. Thirty male Wistar rats were divided into five groups: sham, IR, HFD, HFD + IR, and SP1000 (HFD + IR + spirulina 1000 mg/kg/day; oral gavage). Liver injury, oxidative stress, inflammatory signaling, and inflammasome/pyroptosis-related markers were assessed using serum transaminases, hematoxylin–eosin staining, immunofluorescence, and qRT-PCR. High-fat diet-fed rats developed steatosis, which significantly worsened IR-induced liver damage, as shown by the respective steatosis histological score, the elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and higher expression of inflammatory markers, including Toll-like receptor (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) and inflammasome/pyroptosis-related transcripts, namely NOD-like receptor family pyrin domain-containing 3 (NLRP3), interleukin-18 (IL18), and gasdermin D (GSDMD). Oxidative stress was exacerbated, as reflected by higher levels of malondialdehyde (MDA) and reduced antioxidant defenses (superoxide dismutase (SOD) activity, reduced glutathione (GSH) content, glutathione peroxidase (GPx) expression, and heme oxygenase-1 (HO-1) expression). Furthermore, HFD + IR upregulated sterol regulatory element-binding protein-1c (SREBP-1c) expression and downregulated AMP-activated protein kinase (AMPK) expression. Spirulina supplementation significantly attenuated liver injury and transaminase release, reduced MDA, restored antioxidant parameters, downregulated inflammatory and inflammasome-related gene expression, and shifted both SREBP-1c and AMPK expressions toward control levels. Full article

Systemic infection with Acanthamoeba spp. can induce inflammatory responses within the visual axis, yet the underlying molecular mechanisms in the optic nerve remain poorly understood. The aim of the study was to determine the gene expression of Nlrp3 (encoding NOD-, LRP- and pyrin domain-containing protein 3, NLRP3), Ptgs2 (encoding cyclooxygenase-2, COX-2), Rela (encoding nuclear factor kappa B, NF-κB), and several cytokines in the optic nerve of mice during disseminated infection with Acanthamoeba sp. (T16 genotype) under various immunological conditions. In immunocompetent mice, Ptgs2 and Ifng expressions were upregulated at the beginning of infection. In the late stages, we found increased levels of Il10 and Nlrp3. In immunosuppressed mice, higher expressions of Nlrp3, Ptgs2, Rela, Il1b, Il10, Il17a, Il21, and Ifng were found in the infected mice compared to the control group. These results indicate that immunosuppression promotes prolonged inflammation by altering innate and adaptive immune responses, contributing to sustained neuroinflammatory processes affecting the optic nerve. This study provides mechanistic insight into host–pathogen interactions in the optic nerve during systemic Acanthamoeba infection. Due to the analysis being based on mRNA expression levels, direct inference regarding protein levels and the actual activity of the investigated immunological pathways is limited. Full article

Purpose: To investigate the mechanisms by which plasma extracellular vesicles (EVs) from preterm infants with bronchopulmonary dysplasia (BPD) elicit inflammation and abnormal angiogenesis in neonatal mouse retinas. Methods: EVs from the plasma of 7-day-old preterm infants, born between 23^0/7 and 29^6/7 weeks of gestation, with BPD or without BPD (nBPD) at 36 weeks postmenstrual ages, were adoptively transferred into postnatal day 3 (P3) mice via intravenous retro-orbital sinus injection. Inflammation and pathological neovascularization in neonatal mouse retinas were examined by immunohistochemistry of retinal flat mounts for Allograft Inflammatory Factor 1 (AIF1), CD206, or Glial Fibrillary Acidic Protein (GFAP) and isolectin-B4 (IB4) staining on P17. Retinal inflammation-related transcripts were assessed by qRT-PCR. Proteomic profiles of BPD and nBPD EVs were examined by Liquid Chromatograph Mass Spectrometer/Mass Spectrometer (LC-MS/MS) and Gene Set Enrichment Analysis (GSEA). Results: Adoptively transferred EVs from BPD and nBPD infants crossed the blood–retinal barrier (BRB) in recipient mouse pups. BPD-EVs increased retinal activated microglia, Müller cells, and twisted proliferative neovascularization compared to nBPD-EVs. BPD-EVs also elevated retinal transcripts regulating inflammation and angiogenesis, including NOD-, LRR- and pyrin domain-containing protein 3 (Nlrp3), Apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc), Caspase 3 (Casp3), Caspase 8 (Casp8), Gasdermin D (Gsdmd), Il1β, Il6, Aif1, and Vascular endothelial growth factor (Vegf). Proteomics analysis revealed that BPD-EVs had significantly elevated levels of inflammation and angiogenesis-related proteins compared to nBPD-EVs. Conclusions: BPD-EVs promote inflammation and abnormal neovascularization by upregulating genes related to apoptosis and inflammation in neonatal mouse retinas. EV protein profiles suggest that elevated levels of proteins such as Defensin alpha 1B (DEFA1B), Insulin-like growth factor binding protein 2 (IGFBP2), CD5 antigen-like (CD5L), von Willebrand factor (vWF), and Tenascin C (TNC) in BPD-EVs may contribute to the observed inflammation and angiogenesis. Full article

Background and Objectives: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key innate immune complex, and its aberrant activation contributes to metabolic and neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with anti-inflammatory and metabolic regulatory functions, but its role in NLRP3 inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis remains unclear. The aim of this study was to investigate the effects of BDNF deficiency on LPS- and nigericin-induced NLRP3 inflammasome activation and GSDMD-mediated pyroptosis in vivo, and to elucidate the involvement of NF-κB signaling, autophagy, and ESCRT-III-dependent plasma membrane repair in this process. Materials and Methods: In this in vivo study, male Bdnf ^+/+ and Bdnf ^+/− mice were subjected to lipopolysaccharide (LPS) plus nigericin-induced NLRP3 inflammasome activation. Serum and hippocampus, cortex, liver, epididymal adipose, and muscle tissues were collected 24 h after stimulation for analysis of inflammasome-related, autophagy-related, and membrane repair-related proteins by Western blotting and of serum BDNF, interleukin-1β (IL-1β), and interleukin-18 (IL-18) by ELISA. Results: Bdnf ^+/− mice displayed significantly reduced circulating BDNF levels and exhibited exaggerated LPS plus nigericin-induced increases in IL-1β and IL-18 compared with Bdnf ^+/+ mice. Across all tissues, BDNF deficiency enhanced NF-κB p65, NLRP3, active caspase-1 p20, and GSDMD expression, indicating amplified inflammasome activation and pyroptosis. Conversely, LC3B and SQSTM1/p62 levels were decreased, and VPS4A expression, a key component of the ESCRT-III membrane repair machinery, was suppressed in Bdnf ^+/− mice, suggesting impaired selective autophagy, autophagosome formation, and plasma membrane repair. Conclusions: Together, these findings indicate that BDNF restrains NLRP3 inflammasome activation and GSDMD-mediated pyroptosis through inhibition of NF-κB signaling and coordinated activation of autophagy and ESCRT-III-dependent membrane repair. BDNF thus emerges as an endogenous negative regulator of inflammasome activity and a potential therapeutic target for conditions characterized by aberrant NLRP3-driven inflammation. Full article

Rhizobia are a polyphyletic group of Proteobacteria comprising approximately 700 different species. Despite significant advancements in their taxonomy, evolutionary history, and ecological importance, substantial knowledge gaps remain regarding a detailed understanding of rhizobial biodiversity in a geographical context and the interest in studying and valorizing native rhizobial strains. This bibliometric study used data from the last four decades (1985–2025) to review the taxonomic and functional diversity of the documented novel taxa of rhizobia described from African ecosystems, as well as their valorization status as biofertilizers. It aims to discuss the interest in knowing, preserving, and valorizing native rhizobial resources in the global context of climate change and biodiversity erosion. The study revealed that the first African indigenous novel species of rhizobia was published in 1988, although research on rhizobia dates back to the 1950s in Africa. To date, ~63 species (approximately 9% of the total in the world) and two genera of rhizobia have been described using native isolates from 11 African countries, with substantial discoveries from the Succulent Karoo hotspot of biodiversity in South Africa. Approximately 51% of species are affiliated with Bradyrhizobium and Mesorhizobium, with Vachellia karroo and Senegalia spp. (formerly Acacia spp.) as their primary hosts. Most species-type strains (~89%) were found to be infective on legumes and are good candidates for biofertilizer development. However, there is a limited level of commercial valorization of indigenous isolates as inoculants, mainly because the production of biological intrants is still at the experimental stage in Africa. Interestingly, important breaking point discoveries have been made using native rhizobial strains from Africa, including the pioneering demonstration in 2001 that Burkholderia (beta-rhizobia) is a symbiotic genus with legumes. It also includes the discovery of stem-nodulating rhizobia and Nod factor-independent symbiotic processes in some rhizobia. Together, this review highlights the importance of native African rhizobial strains. This underscores the need to accelerate their agronomic valorization to better support the transition to more resilient and sustainable legume-based farming systems in African countries. Full article

Combination chemotherapy regimens are commonly employed to treat advanced gastric adenocarcinoma (GAC), yet median survival remains less than one year. Nab-paclitaxel has demonstrated significant antitumor activity in preclinical GAC models. Overexpression of growth factors and their receptors is prevalent in GAC and contributes to its pathophysiology, with aberrant activation of the HGF/c-Met pathway reported in up to 50% of patients. We hypothesized that merestinib, a small-molecule inhibitor of c-Met, Axl, and DDR1/2, would enhance the therapeutic response to nab-paclitaxel in GAC. In high c-Met–expressing MKN-45 peritoneal dissemination xenografts in female NOD/SCID mouse models, animal survival was 17 days in controls, 37 days with nab-paclitaxel (118% increase), 24 days with merestinib (41% increase), and 43 days with the combination (153% increase), demonstrating significantly enhanced survival compared with either monotherapy. In MKN-45 subcutaneous xenografts, tumor volumes in the control, nab-paclitaxel, merestinib, and combination groups were 503 mm³, 115 mm³, 91 mm³, and −9.7 mm³ (indicating tumor regression), respectively. In low c-Met-expressing SNU-1 xenografts, tumor volumes were 219 mm³, 105 mm³, 131 mm³, and 57 mm³, respectively. IHC analysis of tumor cell proliferation and microvessel density in MKN-45 tumors supported these findings. In vitro, nab-paclitaxel and merestinib each reduced cell proliferation in GAC-associated cells, with enhanced inhibitory effects when used in combination. In MKN-45 cells, merestinib increased the expression of pro-apoptotic proteins and decreased phosphorylation of c-Met, EGFR, IGF-1R, ERK, and AKT. These results indicate that combining merestinib with nab-paclitaxel may represent a promising therapeutic strategy to improve outcomes for patients with GAC. Full article

Background/Objectives: Silicosis is a chronic disease caused by long-term exposure to high levels of silica dust, which leads to extensive nodular fibrosis in the lungs. The disease is currently a serious occupational health hazard globally. Xuanfei Baidu decoction (XFBD) is a mature Chinese herbal medicine in China that has shown anti-inflammatory and anti-fibrotic effects in mouse experiments, making it a promising candidate for addressing the persistent inflammation and fibrosis in silicosis. Methods: Silicosis was induced in male C57BL/6J mice using crystalline silica (CS). XFBD’s early anti-inflammatory role was verified in vitro in peritoneal macrophages (PMs) and in vivo in silicosis mice, while its late anti-collagen deposition and anti-fibrotic activities were further investigated. Results: In vitro, XFBD effectively inhibits the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in CS-induced lipopolysaccharide (LPS)-primed PMs, decreases the release of inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), and modulates the phenotypic transition of macrophages from the M2 to the M1 phenotype. In vivo studies further validated that XFBD significantly downregulates the expression of NLRP3 and Cleaved-Caspase-1 proteins in the lung tissues of mice afflicted with silicosis. Additionally, XFBD enhanced pulmonary function, inhibited collagen deposition and pulmonary fibrosis in silicosis mice, and reversed epithelial–mesenchymal transition (EMT) by regulating key EMT-related proteins to slow fibrosis. Conclusions: The beneficial effects of XFBD on CS-induced pulmonary fibrosis can be attributed to the induction of macrophage polarization-mediated anti-inflammatory responses during the early stage of fibrotic development, as well as its anti-collagen deposition and anti-fibrotic activities during the intermediate stage of fibrotic development. This study provides preclinical evidence supporting XFBD as a promising candidate for prevention or adjunctive therapy, and its multi-target, time-phase mechanism offers a novel rationale and theoretical foundation for the development of new strategies against silicosis. Full article

Background: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Despite the implementation of the treat-to-target (T2T) strategy and the introduction of several classes of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), a considerable proportion of patients continues to exhibit active, refractory disease. In 2021, the European Alliance of Associations for Rheumatology (EULAR) defined this condition as Difficult-to-Treat Rheumatoid Arthritis (D2T-RA). This study aimed to identify clinical, laboratory, and therapeutic factors associated with D2T-RA. Methods: A total of 344 patients with established RA were retrospectively evaluated. Among them, 164 fulfilled the 2021 EULAR criteria for D2T-RA (D2T group), while 180 did not (NO-D2T group). Clinical (age, sex, disease duration, BMI, smoking, comorbidities), laboratory (RF, ACPA, ESR, CRP), clinimetric (DAS28, CDAI, PhGA, PGA, HAQ), and therapeutic data (glucocorticoid use, methotrexate treatment and dose, monotherapy, advanced therapy exposure, number of failed advanced therapies, current DMARD regimen) were analyzed. Results: Factors significantly associated with D2T-RA included female sex, longer disease duration, higher RF and ACPA titers, elevated ESR levels, glucocorticoid therapy, and a greater number of failed advanced therapies. Although both groups achieved low disease activity or remission by DAS28 and CDAI, JAK inhibitors—particularly Filgotinib and Upadacitinib—were significantly more common in the D2T cohort and appeared associated with clinical stabilization. Conclusions: This study strengthens the understanding of the predictive profile of D2T-RA, confirming the role of disease chronicity and persistent inflammation in the development of treatment resistance. Importantly, the observed trend toward clinical stabilization achieved under JAK inhibitor therapy reinforces their potential to address unmet therapeutic needs in D2T-RA, providing a mechanistically grounded strategy for patients refractory to conventional and biologic DMARDs. Full article

Animal-derived E. faecium poses a public health risk due to its capacity to acquire antimicrobial resistance (AMR) and virulence genes. However, the pathogenicity and cross-host transmission potential of strains originating from unique environments, such as the Qinghai–Tibet Plateau, remain poorly understood. In this study, a strain of E. faecium was isolated from yak feces. We constructed a phylogenetic tree and identified AMR and virulence genes via whole-genome sequencing. Antimicrobial susceptibility testing was performed to determine its resistance phenotype. An in vivo mouse infection model was established to assess pathogenicity, and transcriptomic analysis was utilized to investigate the host’s molecular response mechanisms in infected intestinal tissue. The results indicated that this yak-derived strain is closely related to human clinical isolates, suggesting a risk of cross-host transmission. The strain harbored the AMR genes AAC(6′)-Ii, msrC, and eatAv and exhibited resistance to penicillin, kanamycin, erythromycin, and clindamycin. The strain harbored key virulence genes, such as bopD, Acm, and ClpP. Infection with this strain caused characteristic inflammatory damage in mouse intestinal tissue, as revealed by histopathological examination, including epithelial necrosis, vascular congestion, and inflammatory cell infiltration. Transcriptomics further delineated a complete “Recognition–Response–Damage” signaling axis: pathogen recognition through Toll-like receptors and NOD-like receptors activates the NF-κB and MAPK signaling pathways. This activation is accompanied by significant upregulation of various inflammatory factors and recruits immune cells via chemokine signaling, ultimately leading to tissue damage. Our findings provide insights into the pathogenic pathway of this strain from genetic determinants to phenotypic manifestations, providing a theoretical foundation for assessing the public health risk posed by animal-derived E. faecium and for developing targeted intervention strategies. Full article

Autoimmune type 1 diabetes (T1D) results from the failure of the physiologic regulatory mechanisms that are designed to maintain immune tolerance to pancreatic beta cells. Consequently, the design of strategies to restore tolerance to beta cell antigens is an attractive objective of translational research. We have designed ultrasmall nanoparticles (NPs) loaded with a proinsulin (PI) fusion protein and an agonist for the aryl hydrocarbon receptor (AhR), a transcription factor promoting tolerance induction by different immune cells. We report that a 4 week-treatment with these NPs in non-obese diabetic (NOD) mice starting at disease onset induces temporary and sometimes durable disease remission. Mechanistically, short-term NP treatment induces a rapid depletion of islet infiltrates with a dramatic reduction in the number of CD8⁺ T cells and dendritic cells. This is accompanied by the emergence of B lymphocytes producing IL-10. In the rare mice that undergo durable disease remission, the disappearance of islet infiltrates is associated with the emergence of Foxp3⁺ CD4⁺ regulatory T cells, IFN-γ-producing memory T cells in the spleen, and draining lymph nodes (LNs). We conclude that treatment with these NPs could be of interest in the treatment of recent-onset autoimmune diabetes, but is unlikely to be sufficient for the induction of long-term remission as a stand-alone therapy. Full article

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1/3 (SIRT1/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-κB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub–axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling. Full article

Nucleated erythroid cells (NECs) have emerged as active participants in immune responses in addition to their canonical oxygen transport function. The subpopulations and immune heterogeneity of chick erythroid cells (ch-ECs) upon infection have not been fully characterized. Single-cell RNA sequencing (scRNA-seq) was used to profile ch-ECs in chicks infected with avian pathogenic Escherichia coli (APEC). Unsupervised clustering uncovered ten distinct ch-EC subpopulations (C1–C10), with significant compositional shifts between infected and control groups. Pseudotime analysis revealed a developmental continuum: C1, C3, C5, and C9 as early progenitors; C2, C4, C6, C7, and C10 as mature erythroid cells; and C8 as a naive population. We revealed 62 immune-related genes, including protein kinases and heat shock proteins, and subpopulation-specific differentially expressed genes (DEGs) linked to immune functions. SCENIC analysis revealed Fos, Srf, and Stat3 as key transcription factors with elevated regulon activity and specificity following infection. Subpopulations C2, C4, C6, and C7, which exhibited marked abundance changes, were scrutinized for immune relevance through integrated multi-omics analysis. Immune-related genes including FOS, AKAP9, HS6ST1, GAB3, TFRC, HSPA8, HSP90AA1, and DNAJB6 were identified. Enrichment analysis indicated activation of the MHC class I antigen presentation pathway, while pathways such as Mitogen-Activated Protein Kinase (MAPK) signaling, NOD-like receptor (NLR) signaling, and the heat shock response were found to be suppressed. In conclusion, this study delineates the immune gene repertoire and signaling networks of ch-ECs during APEC infection, offering new perspectives on NEC immunoregulatory functions. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains a high-burden disease worldwide with increasing incidence, poor prognosis, and high mortality. Complete surgical resection is the only potentially curative treatment; however, due to a lack of symptoms in the early stages, most patients have advanced disease when diagnosed. Type 2 diabetes mellitus (T2DM) is a significant health concern characterized by hyperglycemia, insulin resistance, and impairment in insulin secretion. T2DM is linked with PDAC, sharing a complex bidirectional relationship. Therefore, dual causality between the two diseases represents significant challenges in practice, distinguishing existing T2DM as a PDAC risk factor from newly onset, potentially pancreatic cancer-related diabetes (PCRD). Evidence showed that new-onset diabetes (NOD) may serve as a biomarker for early diagnosis of PDAC, and several risk prediction models were developed to identify high-risk patients for further intervention. Although early PDAC detection is important, widespread screening is not currently recommended for T2DM patients due to a lack of cost-effective, efficient screening modalities. However, further risk stratification in diabetic patients is warranted to support a targeted screening strategy with economic viability. Diabetes confers ≈2-fold PDAC risk overall, with the highest relative risk in the first 2–3 years after diagnosis. Strategies using clinical signs (age ≥50–60 years, unintentional weight loss, rapid HbA1c escalation/insulin initiation) and predictive risk scores (e.g., ENDPAC) can triage NOD patients for magnetic resonance imaging/computed tomography (MRI/CT) and endoscopic ultrasound (EUS). A targeted screening approach may allow early diagnosis that could improve the prognosis of PDAC patients. This narrative review aims to synthesize current evidence linking T2DM and PDAC; delineate risk factors within diabetes populations; appraise predictive models and biomarkers for differentiating PCRD from typical T2DM; outline pragmatic, risk-adapted screening strategies, especially for NOD, and identify additional areas where further research is needed. Full article