Prospective comparison of two surgical approaches for incarcerated and strangulated inguinal hernia: preperitoneal hernioplasty through the lower abdominal median incision and laparoscope (TAPP).

The optimal surgical approach of incarcerated and strangulated inguinal hernia is controversial. Retrospective studies showed that surgical approaches through lower abdominal median incision or laparoscopic are superior to the oblique inguinal incision, respectively. Whether transabdominal laparoscopic approach is superior to the lower abdominal median incision approach needs prospective research.Prospective comparative study of patients with incarcerated and strangulated groin hernia admitted to Jinshan hospital for emergency surgery from January 2018 to June 2022. They were divided into two groups according to different surgical approach. The open preperitoneal repair group (OPR) was operated through the lower abdominal median incision. Laparoscopic preperitoneal repair group (TAPP) was completed under transabdominal laparoscope. The perioperative complications and long-term results of the two groups were compared and analyzed. Eighty-two patients met the inclusion criteria, 40 in OPR group and 42 in TAPP group. Baseline data of the two groups were comparable. Thirteen cases (15.9%) of the two groups underwent intestinal resection and anastomosis. Seventy cases (90.2%) underwent the 1st stage mesh repair, including 5 cases of preperitoneal hernioplasty after intestinal resection. The average operation time of TAPP group was 13 min longer (60.7 ± 13.7 min vs 47.8 ± 19.8 min P < 0.001), and the visual analogue scale pain score at 24 h after operation was lower (3.5 ± 1.2 vs 4.4 ± 1.7 P = 0.019) than that of OPR group. There was 1 case of bladder injury (2.5%) in OPR group and 1 case of inferior abdominal artery injury (2.4%) in TAPP group. There was no difference in the rate of the 1st stage hernioplasty between the two groups. In OPR group, 2 cases (5%) extended the incision for more than 2 cm, while in TAPP group, 1 case (2.4%) converted to laparotomy. The time of hospital stay (3.2 ± 1.8 d vs 4.3 ± 2.7 d, P = 0.036) and return to normal activities (7.9 ± 2.7 d vs 11.0 ± 4.4 d, P < 0.001) were shorter in TAPP group. The rate of total postoperative complications including chronic pain, surgical-site infection, seroma, hernia recurrence and so on was 11.9% in TAPP group, which was not significantly different from 25% in OPR group (P = 0.212). There were no cases of mesh related infection and death within 30 days in both groups.TAPP is safe and feasible for the operation of acute incarcerated inguinal hernia. TAPP had better comfort and faster recovery over open preperitoneal repair for the appropriate patients with incarcerated/strangulated inguinal hernia, which can reduce acute pain, shorten hospital stay and return to normal activities earlier.

Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers.

Ferroptosis is a promising therapeutic target for injury-related diseases, yet diversity in ferroptosis inhibitors remains limited. In this study, initial structure optimization led us to focus on the bond dissociation enthalpy (BDE) of the N-H bond and the residency time of radical scavengers in a phospholipid bilayer, which may play an important role in ferroptosis inhibition potency. This led to the discovery of compound D1, exhibiting potent ferroptosis inhibition, high radical scavenging, and moderate membrane permeability. D1 demonstrated significant neuroprotection in an oxygen glucose deprivation/reoxygenation (OGD/R) model and reduced infarct volume in an in vivo stroke model upon intravenous treatment. Further screening based on this strategy identified NecroX-7 and Eriodictyol-7-O-glucoside as novel ferroptosis inhibitors with highly polar structural characteristics. This approach bridges the gap between free radical scavengers and ferroptosis inhibitors, providing a foundation for research and insights into novel ferroptosis inhibitor development.

Discovery of orally bioavailable phenyltetrazolium derivatives for the acute treatment and the secondary prevention of ischemic stroke.

The potential for secondary stroke prevention, which can significantly reduce the risk of recurrent strokes by almost 90%, underscores its critical importance. N-butylphthalide (NBP) has emerged as a promising treatment for acute cerebral ischemia, yet its efficacy for secondary stroke prevention is hindered by inadequate pharmacokinetic properties. This study, driven by a comprehensive structural analysis, the iterative process of structure optimization culminated in the identification of compound B4, which demonstrated exceptional neuroprotective efficacy and remarkable oral exposure and oral bioavailability. Notably, in an in vivo transient middle cerebral artery occlusion (tMCAO) model, B4 substantially attenuated infarct volumes, surpassing the effectiveness of NBP. While oral treatment with B4 exhibited stronger prevention potency than NBP in photothrombotic (PT) model. In summary, compound B4, with its impressive oral bioavailability and potent neuroprotective effects, offers promise for both acute ischemic stroke treatment and secondary stroke prevention.

Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML.

AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3, featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC50 value of 18.73 ± 10.78 nM, and stimulated 72.77 ± 3.51 % cell differentiation at 6.25 nM in HL-60 cells. Moreover, C3 exhibited potent anti-proliferative activity against various AML cell types. Degradation selectivity analysis indicated that C3 could be endowed with efficient degradation of CDK2/4/6/9 and FLT3, especially FLT3-ITD in MV4-11 cells. These findings propose that C3 combined targeting CDK2/4/6/9 and FLT3 with enhanced differentiation and proliferation inhibition, which holds promise as a potential treatment for AML.

Andrographolide Improves ApoE4-Mediated Blood-Brain Barrier Injury by Alleviating Inflammation.

The pathological and physiological studies of Alzheimer's disease (AD) have been in-depth, and apolipoprotein E4 (ApoE4) has been proven to be highly correlated with AD, and clinical and experimental data show that ApoE4 can cause blood-brain barrier (BBB) injury, and the change of BBB permeability is an important factor affecting the development of AD. Andrographolide (Andro), as the active component of the natural plant Andrographis paniculata, has been proven to have anti-inflammatory and antioxidant effects, which have potential neuroprotective effects. To verify the protective effect of Andro on BBB in a short term, our research group used atorvastatin (Atorva)-mediated zebrafish brain injury model and the ApoE4-mediated cell co-culture model of BBB injury to explore the protective effects and mechanisms of Andro on BBB injury. Studies have shown that Andro can inhibit the activation of CypA/NF-κB/MMP-9 signaling pathway and has achieved the effect of antagonizing the inhibition of ApoE4 on intercellular tight junction proteins (occludin, claudin-5, and ZO-1). At the same time, Andro can inhibit the secretion of cell adhesion molecules (VCAM-1 and ICAM-1) in cells, thereby delaying the occurrence and progression of neuroinflammation and playing a protective role in BBB. In conclusion, Andro is a potent natural product which can protect the blood-brain barrier.

Photoinduced arylation or alkylation of 1,2,4-triazine-3,5(2H,4H)-diones with hydrazines.

A light-induced method is developed for synthesizing azauracils. This method is independent from traditional methodology. Remarkably, this reaction can also be powered by sunlight. The applicability of this method is further demonstrated through its successful implementation in large-scale reactions and its use in synthesizing derivatives.

Ruxolitinib attenuates microglial inflammatory response by inhibiting NF-κB/MAPK signaling pathway.

Neuroinflammation is involved in the physiological and pathological processes of numerous neurological diseases, and its inhibition seems to be a promising therapeutic direction for these diseases. Ruxolitinib is a classical Janus kinase (JAK) inhibitor that is oral, highly potent and bioavailable, which has recently gained approval from the US Food and Drug Administration (FDA) for the treatment of inflammatory disorders. The potential inhibitory effect of ruxolitinib on neuroinflammation has not been fully studied. In the lipopolysaccharide (LPS) induced neuroinflammatory cell model, we observed that ruxolitinib reduced the levels of IL-1ß, IL-6 and tumor necrosis factor-α (TNF-α) expression, and neuroinflammation by inhibiting the Mitogen-Activated Protein Kinase/Nuclear factor-κ B (MAPK/NF-κB) signaling pathway. Similarly, mice injected intracerebroventricular with ruxolitinib exhibited significantly reduced LPS-stimulated activation of microglia and astrocytes, and expression of proinflammatory cytokine IL-1ß, TNF-α and IL-6. These results demonstrate that ruxolitinib attenuates the neuroinflammatory responses both in vivo and in vitro, at least in part by inhibiting MAPK/NF-κB signaling pathway. Our findings suggest that ruxolitinib may serve as a potential drug for the treatment of microglia-mediated neuroinflammation.

Discovery of novel, potent, selective and orally bioavailable HPK1 inhibitor for enhancing the efficacy of anti-PD-L1 antibody.

Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase in the MAP4K family, is expressed predominantly in immune cells, and has been identified as a negative regulator of immune signaling. Accumulating evidences demonstrated that loss of HPK1 kinase function effectively enhances anti-tumor responses. In this study, we disclose the medicinal chemistry campaigns to discovery potent, selective, and orally active HPK1 inhibitors, starting from our previous work based on rigidification strategy. Systematically structure-activity relationship (SAR) exploration led to the identification of F03 (HMC-B17). The representative compound, HMC-B17, showed the potent HPK1 inhibition with an IC50 value of 1.39 nM and favorable selectivity against TCR-related kinases. In addition, the HMC-B17 effectively enhanced the IL-2 secretion in Jurkat cells (EC50 = 11.56 nM). Strikingly, immune-reverse effects and improved immune response in vivo were observed after HMC-B17 treatment. Furthermore, HMC-B17 combined with anti-PD-L1 antibody demonstrated a synergistic antitumor efficacy with TGI% value of 71.24 % in CT26 model. Collectively, our findings suggest that HMC-B17 could be a valuable lead compound to develop a safe and potent HPK1 inhibitor for further cancer immunotherapy.

The progress of small molecules against cannabinoid 2 receptor (CB2R).

The two subtypes of cannabinoid receptors (CBR), namely CB1R and CB2R, belong to the G protein-coupled receptor (GPCR) superfamily and are confirmed as potential therapeutic targets for a variety of diseases such as inflammation, neuropathic pain, and immune-related disorders. Since CB1R is mainly distributed in the central nervous system (CNS), it could produce severe psychiatric adverse reactions and addiction. In contrast, CB2R are predominantly distributed in the peripheral immune system with minimal CNS-related side effects. Therefore, more attention has been devoted to the discovery of CB2R ligands. In view of the favorable profile of CB2R, many high-binding affinity and selectivity CB2R ligands have been developed recently. This paper reviews recent research progress on CB2R ligands, including endogenous CB2R ligands, natural compounds, and novel small molecules, in order to provide a reference for subsequent CB2R ligand development.

Nuciferine reduces inflammation induced by cerebral ischemia-reperfusion injury through the PI3K/Akt/NF-κB pathway.

BACKGROUND: Cerebral ischemia has the characteristics of high incidence, mortality, and disability, which seriously damages people's health. Cerebral ischemia-reperfusion injury is the key pathological injury of this disease. However, there is a lack of drugs that can reduce cerebral ischemia-reperfusion injury in clinical practice. At present, a few studies have provided some evidence that nuciferine can reduce cerebral ischemia-reperfusion injury, but its specific mechanism of action is still unclear, and further research is still needed. OBJECTIVE: In this study, PC12 cells and SD rats were used to construct OGD/R and MCAO/R models, respectively. Combined with bioinformatics methods and experimental verification methods, the purpose of this study was to conduct a systematic and comprehensive study on the effect and mechanism of nuciferine on reducing inflammation induced by cerebral ischemia-reperfusion injury. RESULTS: Nuciferine can improve the cell viability of PC12 cells induced by OGD/R, reduce apoptosis, and reduce the expression of inflammation-related proteins; it can also improve the cognitive and motor dysfunction of MCAO/R-induced rats by behavioral tests, reduce the area of cerebral infarction, reduce the release of inflammatory factors TNF-α and IL-6 in serum and the expression of inflammation-related proteins in brain tissue. CONCLUSION: Nuciferine can reduce the inflammatory level of cerebral ischemia-reperfusion injury in vivo and in vitro models by acting on the PI3K/Akt/NF-κB signaling pathway, and has the potential to be developed as a drug for the treatment of cerebral ischemia-reperfusion injury.

Discovery of highly efficient CRBN-recruiting HPK1-PROTAC as a potential chemical tool for investigation of scaffolding roles in TCR signaling.

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a promising target for immune-oncology therapy. It has been recently demonstrated that loss of HPK1 kinase activity can enhance T cell receptor (TCR) signaling. However, many essential functions mediated by the HPK1 scaffolding role are still beyond the reach of any kinase inhibitor. Proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for pathogenic proteins degradation with the characteristics of rapid, reversible, and low-cost versus RNA interference or DNA knock-out technology. Herein we first disclosed the design, synthesis, and evaluation of a series of thalidomide-based PROTAC molecules and identified B1 as a highly efficient HPK1 degrader with DC50 value of 1.8 nM. Further mechanism investigation demonstrated that compound B1 inhibits phosphorylation of the SLP76 protein with IC50 value of 496.1 nM, and confirmed that B1 is a bona fide HPK1-PROTAC degrader. Thus, this study provides a basis for HPK1 degraders development and the candidate could be used as a potential chemical tool for further investigation of the kinase-independent signaling of HPK1 in TCR.

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.

A hybrid energy-based and AI-based screening approach for the discovery of novel inhibitors of JAK3.

The JAKs protein family is composed of four isoforms, and JAK3 has been regarded as a druggable target for the development of drugs to treat various diseases, including hematologic tumors, cancer, and neuronal death. Therefore, the discovery of JAK3 inhibitors with novel scaffolds possesses the potential to provide additional options for drug development. This article presents a structure-based hybrid high-throughput virtual screening (HTVS) protocol as well as the DeepDock algorithm, which is based on geometric deep learning. These techniques were used to identify inhibitors of JAK3 with a novel sketch from a specific "In-house" database. Using molecular docking with varying precision, MM/GBSA, geometric deep learning scoring, and manual selection, 10 compounds were obtained for subsequent biological evaluation. One of these 10 compounds, compound 8, was found to have inhibitory potency against JAK3 and the MOLM-16 cell line, providing a valuable lead compound for further development of JAK3 inhibitors. To gain a better understanding of the interaction between compound 8 and JAK3, molecular dynamics (MD) simulations were conducted to provide more details on the binding conformation of compound 8 with JAK3 to guide the subsequent structure optimization. In this article, we achieved compound 8 with a novel sketch possessing inhibitory bioactivity against JAK3, and it would provide an acceptable "hit" for further structure optimization and modification to develop JAK3 inhibitors.

Current advances and development strategies of orally bioavailable PROTACs.

Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last half decade, we have witnessed several PROTACs initiated phase I/II/III clinical trials, which inspired us a lot. However, the structure of PROTACs beyond "rule of 5" resulted in developing PROTACs with acceptable oral pharmacokinetic (PK) properties remain one of the biggest bottleneck tasks. Many reports have demonstrated that it is possible to access orally bioavailable PROTACs through rational ligand and linker modifications. In this review, we systematically reviewed and highlighted the most recent advances in orally bioavailable PROTACs development, especially focused on the medicinal chemistry campaign of discovery process and in vivo oral PK properties. Moreover, the constructive strategies for developing oral PROTACs were proposed comprehensively. Collectively, we believe that the strategies summarized here may provide references for further development of oral PROTACs.

Lysosome and related protein degradation technologies.

Recently, targeted protein degradation technologies based on lysosomal pathways have been developed. Lysosome-based targeted protein degradation technology has a broad range of substrates and the potential to degrade intracellular and extracellular proteins, protein aggregates, damaged organelles and non-protein molecules. Thus, they hold great promise for drug R&D. This study has focused on the biogenesis of lysosomes, their basic functions, lysosome-associated diseases and targeted protein degradation technologies through the lysosomal pathway. In addition, we thoroughly examine the potential applications and limitations of this technology and engage in insightful discussions on potential avenues for future research. Our primary objective is to foster preclinical research on this technology and facilitate its successful clinical implementation.

Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion.

Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC50 = 1.11 nM) and highly selectivity profile. Compound HMC-H8 also exhibited robust inhibition of p-SLP 76 (IC50 = 283.0 nM) and promotion IL-2 release (EC50 = 157.08 nM), and INF-γ production in a dose-dependent manner in vitro assays. Strikingly, HMC-H8 shown effective immune reversal response in immunesuppressive condition. Moreover, Compound HMC-H8 displayed acceptable metabolic stability (T1/2 = 56.87 min), along with low CYP450 inhibition in human liver microsomes and good oral bioavailability (F = 15.05%) in rat. Furthermore, HMC-H8 was found to modulate the expression of c-Myc in Western blotting experiments. Taken together, this study provides new potent HPK1 inhibitors for further anticancer drug discovery based on immuno-oncology.

Discovery of novel pyrrolo [2,3-d] pyrimidine derivatives as potent FAK inhibitors based on cyclization strategy.

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a pivotal role in tumor invasion and metastasis. Many FAK inhibitors had been reported, but the development of FAK inhibitors in clinical studies are still limited. To facilitate the discovery of FAK modulators and further elucidate the role of FAK in cancer metastasis, it is necessary to discover a novel, potent and selective FAK inhibitor. In this study, a series of FAK inhibitors with novel scaffold were designed and synthesized based on cyclization strategy. Here, we reported compound 10b (HMC-18NH) with excellent inhibition of FAK (IC50 = 9.9 nM) and anticancer activity against several cancer cell lines including BxPC-3, PANC-1, MCF-7, MDA-MB-231, U-87MG, HepG2, HCT-15 and A549. Extraordinary, compound 10b showed the best cytotoxic effects against A549 with the IC50 value of 0.8 µM. In addition, 10b exhibited effective invasion and migration suppression in A549 cells. Further investigations revealed that compound 10b potently induced and promoted apoptosis in a dose-dependent manner and arrested A549 cells in the G2/M phase. Collectively, these results suggest that 10b is a promising FAK inhibitor and serve as a lead compound which deserve for further optimization.

The progress of molecules and strategies for the treatment of HBV infection.

Hepatitis B virus infections have always been associated with high levels of mortality. In 2019, hepatitis B virus (HBV)-related diseases resulted in approximately 555,000 deaths globally. In view of its high lethality, the treatment of HBV infections has always presented a huge challenge. The World Health Organization (WHO) came up with ambitious targets for the elimination of hepatitis B as a major public health threat by 2030. To accomplish this goal, one of the WHO's strategies is to develop curative treatments for HBV infections. Current treatments in a clinical setting included 1 year of pegylated interferon alpha (PEG-IFNα) and long-term nucleoside analogues (NAs). Although both treatments have demonstrated outstanding antiviral effects, it has been difficult to develop a cure for HBV. The reason for this is that covalently closed circular DNA (cccDNA), integrated HBV DNA, the high viral burden, and the impaired host immune responses all hinder the development of a cure for HBV. To overcome these problems, there are clinical trials on a number of antiviral molecules being carried out, all -showing promising results so far. In this review, we summarize the functions and mechanisms of action of various synthetic molecules, natural products, traditional Chinese herbal medicines, as clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR/Cas)-based systems, zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), all of which could destroy the stability of the HBV life cycle. In addition, we discuss the functions of immune modulators, which can enhance or activate the host immune system, as well some representative natural products with anti-HBV effects.

Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer's disease.

The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer's disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-ß (Aß). Thus, targeting the τ-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the τ-protein and the E3 ligase. The molecules were examined in vitro, and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound I3 in healthy rats. Our data showed that compound I3 could effectively degrade τ-protein, reduce Aß-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD.

Expression, Clinical Significance, Immune Infiltration, and Regulation Network of miR-3940-5p in Lung Adenocarcinoma Based on Bioinformatic Analysis and Experimental Validation.

Background: Based on bioinformatics analysis and experimental validation, we investigated the expression, clinical significance, immune infiltration, and potential signaling pathways of miR-3940-5p in lung adenocarcinoma (LUAD). Methods: 521 LUAD tissue samples and 46 normal lung tissue samples from The Cancer Genome Atlas (TCGA) database. We evaluated the relationship between clinical features and miR-3940-5p expression using Kruskal-Wallis, Wilcoxon sign-rank, and logistic regression, explored the relationship between miR-3940-5p expression and the prognosis of LUAD patients using Kaplan-Meier survival curve analysis. Several databases were used to identify miRNA targets. MiR-3940-5p target genes were analyzed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The significant role of miR-3940-5p in function was evaluated using immune infiltration analysis. LUAD cell lines were tested for miR-3940-5p expression using QRT-PCR. Results: There was a significant association between high miR-3940-5p expression in LUAD and T stage (P=0.005), pathologic stage (P=0.047), race (White vs Asian & Black or African American) (P=0.041), residual tumor (P=0.043), and anatomic neoplasm subdivision2 (P=0.030). MiR-3940-5p expression predicted poor overall survival (HR: 1.35; 95% CI: 1.01-1.81; P=0.045), disease-specific survival (HR: 1.53; 95% CI: 1.05-2.23; P=0.026), and progression-free survival (HR: 1.35; 95% CI: 1.03-1.77; P=0.032). BAP1, BBS1, CCR2, KCNE3, PEBP1, and RABL2A were all associated with poor OS in LUAD patients with low miR-3940-5p expression levels. According to GO and KEGG analyses, miR-3940-5p may play a role in LUAD development by regulating pathways such as measles, PI3K-Akt signaling pathway, and p53 signaling pathway. There was a correlation between the expression level of miR-3940-5p and immune infiltration. LUAD cell lines showed significantly higher levels of miR-3940-5p than Beas-2B cells. Conclusion: A high expression of miR-3940-5p is significantly associated with a poor prognosis in patients with LUAD, suggesting that it could be used as a prognostic biomarker.