Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide due to its high rates of recurrence and metastasis. This underscores the urgent need to develop innovative drugs and treatment strategies to improve patient outcomes. This study examined the molecular pathways underlying troxerutin's therapeutic potential in HCC, providing information that could aid in the development of novel therapeutic strategies. Cell proliferation and apoptosis were assessed using CCK-8, EdU assays, and flow cytometry. Protein expression and mRNA alterations were analyzed by Western blotting and PCR, respectively. Cell migration and invasion were evaluated using Transwell assays, while tumor cell stemness was examined through sphere formation assays. Troxerutin's functional role was studied using in vivo models. Proteomic profiling of troxerutin-treated cells was performed using iTRAQ combined with LC-MS/MS to identify differentially expressed proteins (DEPs). Furthermore, luciferase reporter and ChIP assays were conducted to elucidate the underlying regulatory mechanisms. These findings demonstrate that troxerutin markedly inhibits HCC malignancy and stemness in both in vitro and in vivo models. Bioinformatics analysis indicated that the FOXO and SYK signaling pathways were predominantly enriched among the differentially expressed proteins. Mechanistically, we show that Syk dephosphorylation activates FOXO3 and facilitates its translocation into the nucleus. Moreover, we confirm that FOXO3 directly associates with the Syk promoter, thereby initiating its transcription. The present study reveals that troxerutin attenuates HCC progression by targeting the FOXO3/Syk feedback loop, inhibiting the stem-like properties of HCC cells.

A key factor that limits the therapeutic benefits for non-small cell lung cancer (NSCLC) patients is chemoresistance. Even so, a detailed understanding of the process involved in chemoresistance acquisition and development at molecular level in NSCLC is still lacking. Here, we established chemo-resistant NSCLC cells with obvious resistance to vincristine and paclitaxel and found the abnormal up-regulation of Carnitine O-Octanoyltransferase (CROT) in these cells by means of transcriptomics. In vitro and in vivo experiments demonstrate that the survival of NSCLC cells, especially chemosensitivity, including sensitivity to chemotherapeutics beyond vincristine and paclitaxel, was markedly influenced by CROT expression, and CROT silencing even reversed chemoresistance in NSCLC. Mechanistically, CROT is overactivated within peroxisomes in chemo-resistant NSCLC cells and drives chemoresistance relying on its involvement in lipid metabolism and oxidative stress processes. By mediating the production of Hydrogen Peroxide (H2O2) and reactive oxygen species (ROS), CROT stabilizes eryth-like-2 associated factor 2 (Nrf2) via preventing its ubiquitination and degradation, leading to more nuclear translocation of Nrf2, thereby inhibiting chemotherapy stress-induced ferroptosis. Accordingly, fatty acid oxidation inhibitors or ferroptosis activators rendered NSCLC cells increased sensitivity to chemotherapy in vitro and in vivo. Clinically and encouragingly, the aberrant up-regulation of CROT and Nrf2 was observed in chemo-resistant NSCLC tumor tissues and patients with higher CROT and/or Nrf2 level possessed a poor outcome. In sum, our study identifies CROT as a key promoter to drive chemoresistance of NSCLC cells by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis. The targeted inhibition of this axis and associated components individually or in cascades combined with chemotherapy may be exploited in avoiding or overcoming chemoresistance in NSCLC.

Lung adenocarcinoma (LUAD) displays marked intratumoral heterogeneity with distinct histological patterns. The solid pattern representing poorly differentiated LUAD is linked to poor prognosis and therapeutic resistance. To uncover underlying mechanisms, we integrate bulk and single-cell RNA sequencing and identify a preferential enrichment of interleukin 4 induced 1 (IL4I1)-expressing tumor-associated macrophages (TAMs) and tryptophan 2,3-dioxygenase (TDO2)-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) in a solid pattern of LUAD. Spatial transcriptomics reveals their co-localization in peritumoral stroma, forming an immune-excluded niche. Mechanistically, TDO2⁺ myCAFs promoted monocyte-to-IL4I1⁺ TAM differentiation via the kynurenine-aryl hydrocarbon receptor (AhR) axis. Tryptophan metabolomic landscapes confirm that IL4I1⁺ TAMs and TDO2⁺ myCAFs enhance tryptophan degradation and accumulation of AhR ligands (e.g., kynurenine, indole-3-carboxaldehyde), contributing to CD8⁺ T cell exhaustion and anti-PD-1 therapeutic resistance. IL4I1⁺ TAMs and TDO2⁺ myCAFs conformably mediate ferroptosis resistance through the AhR-NRF2-GPX4-SLC7A11 pathway. Notably, AhR antagonist CH-223191 restores ferroptosis sensitivity of tumor cells. A triple therapy combining CH-223191, ferroptosis inducer (Imidazole ketone erastin or RSL3), and anti-PD-1 agent demonstrates superior efficacy and safety in vivo. Together, our findings demonstrate that IL4I1⁺ TAMs and TDO2⁺ myCAFs synergistically establish an immunosuppressive, ferroptosis-resistant niche via AhR signaling in solid predominant LUAD and offer promising therapeutic strategies to reprogram the tumor microenvironment.

Cardiovascular diseases (CVDs) are characterized by high morbidity and mortality rates, imposing substantial epidemiological and economic burdens worldwide. Among the multifaceted mechanisms implicated in CVDs, autophagy and ferroptosis, two intimately linked cellular processes, emerge as pivotal pathophysiological contributors. Autophagy, as an evolutionary conserved process that mediates the degradation and recycling of intracellular components, including proteins and organelles, exerts critical regulatory effects on iron metabolism and lipid homeostasis through various specialized forms, including ferritinophagy and lipophagy. Conversely, ferroptosis, an iron dependent form of cell death, involves oxidative stress and the accumulation of lipid peroxides, often triggered by iron overload and the dysfunction of glutathione peroxidase 4 (GPX4). The intricate crosstalk between these two processes, particularly ferritinophagy-mediated iron regulation influencing ferroptosis, plays a crucial role in diverse CVDs contexts. Key regulatory molecules, such as Beclin-1 and nuclear factor E2-related factor 2 (Nrf2), function as central hubs, orchestrating the intricate interplay between autophagy and ferroptosis. Through a comprehensive examination of these mechanisms across various CVDs pathologies, we summarize the latest findings and outline potential therapeutic strategies targeting the crosstalk between autophagy and ferroptosis. As the inaugural review focusing on autophagy-ferroptosis interactions in CVDs, this work significantly enriches our understanding of the pathophysiology of CVDs and identifies novel therapeutic targets with potential for precision medicine interventions in managing CVDs.

Lung cancer is a malignant tumor of the bronchial mucosa or gland, the morbidity and mortality increase rapidly, and it is a great threat to human health and life. Propofol is a short-acting intravenous anesthetic, and its effect on lung cancer has been studied, but the mechanism is not thorough. The 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), 5-ethynyl-2’-deoxyuridine (EdU) staining, flow cytometry, and transwell assays were applied to assess the viability, proliferation, apoptosis, and invasion, respectively. The glycolytic analysis was performed using the corresponding kits. The gene expression was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. The interaction between genes was obtained from the STRING database or ubiquitination analysis. The xenograft tumor mouse models were established to verify the effects of propofol in vivo, and IHC was adopted to detect the gene expression in vivo. In this study, we found that propofol impeded lung cancer progression and glycolysis. Additionally, propofol curbed the triosephosphate isomerase 1 (TPI1) protein and increased TPI1 ubiquitination modification, meanwhile, propofol exerted inhibitory functions in lung cancer through TPI1. Besides, the protein stability and ubiquitination modification of TPI1 were mediated by ubiquitin-specific peptidase 5 (USP5), and USP5 expedited the progression and glycolysis of lung cancer via TPI1. In the meantime, propofol modulated USP5-regulated functions in lung cancer. In vivo, propofol-inhibited tumor growth by regulating USP5-mediated TPI1. This study presents propofol/USP5/TPI1 curbing glycolysis metabolism and tumor growth in lung cancer, indicating that propofol-mediated ubiquitination of the target gene may be a new therapeutic target for lung cancer. Propofol inhibits lung cancer cell proliferation, invasion, and glycolysis and promotes apoptosis in vitro, as well as blocks tumor growth in vivo by mediating USP5-modulated TPI1 deubiquitination.

Small cell lung cancer (SCLC) is an intractable disease with rapid progression and high mortality, presenting a persistent obstacle impeding clinical management. Although recent advancements in immunotherapy have enhanced the response rates of platinum-based chemotherapy regimens, the emergence of acquired resistance invariably leads to recurrence and metastasis. Consequently, there is an urgent necessity to explore novel therapeutic targets and optimize existing treatment strategies. This article comprehensively reviews the currently available therapeutic modalities for SCLC. It delves into the immunologic prognostic implications by analyzing selected immune-related signatures. Moreover, it conducts an in-depth exploration of the molecular subtyping of SCLC and the associated molecular pathways to identify potential therapeutic targets. Specifically, the focus is on clinical interventions targeting delta-like ligand 3 (DLL3), elucidating its resistance mechanisms and demonstrating its notable antitumor efficacy. Furthermore, the study examines the mechanisms of chimeric antigen receptor (CAR) T and antibody-drug conjugate (ADC), covering resistance issues and strategies for optimizing resistance management, with particular emphasis being placed on analyzing the prospects and clinical value of CAR T therapy in the context of SCLC. Moreover, the effectiveness of poly ADP-ribose polymerase and ataxia telangiectasia and rad3/checkpoint kinase 1 inhibitors is discussed and underscores the advantages of combining these inhibitors with standard chemotherapy to combat chemoresistance and enhance the antitumor effects of immunotherapies. Overall, this study investigates emerging strategies for targeted therapies and optimized combination regimens to overcome resistance in SCLC and highlights future strategies for new therapeutic technologies for SCLC.

Hepatocellular carcinoma (HCC) is a highly invasive disease, and advanced tumours are often accompanied by a poor prognosis; thus, the treatment of advanced HCC is still based on comprehensive treatment. Bupleurum chinensis DC. (Chaihu) is widely used in the treatment of liver cancer in traditional Chinese medicine. However, few studies have explored the mechanism of action of Chaihu in hepatocellular carcinoma or its impact on prognosis. The core target was obtained by matching differentially expressed genes (DEGs) in HCC tissues to targets associated with Chaihu. These targets were used to identify HCC subtypes and build prognostic models for patients with HCC. We also explored the immune microenvironment and enrichment pathways between different clusters. The LASSO(The Least Absolute Shrinkage and Selection Operator) regression model was used to establish a risk-score model composed of four hub genes. The Kaplan-Meier curve showed significant differences in survival between the high- and low-risk groups. The risk-score model was then combined with clinical information to develop a nomogram to predict patient survival. Finally, three hub genes identified in the prognostic model were verified using in vitro experiments. We screened 77 prognostically relevant DEGs and selected four genes for the risk score model. Multivariate regression analysis revealed that the risk score model was an independent prognostic factor. The survival rate was significantly lower for the high-risk group than for the low-risk group (P < 0.05). In vitro experiments showed that the compounds present in Chaihu decreased the expression of prognostic genes. The combination of prognostic analysis and cell experiments showed that Chaihu exerted a potential therapeutic effect on hepatocellular carcinoma. This study established a risk-scoring model for Chaihu-related genes and evaluated its effectiveness at determining the characteristics of Chaihu that are favourable for the prognosis of liver cancer. Chaihu improved the prognosis by acting on three core prognostic genes (MMP1, NQO1, and PLK1) and the immune microenvironment, thus benefiting patients with HCC.

The continued rise in recurrence and mortality rates of cervical cancer suggests the need to find novel therapeutic targets. Previous studies suggest that TRIP4 acts as a transcription factor to regulate cervical carcinogenesis and progression. Our aim was to explore whether the key downstream genes of TRIP4 functions same as TRIP4 in promoting cervical cancer development. We analyzed and confirmed the downstream targets of TRIP4 by RNA sequencing in cervical cancer cells with TRIP4 knockdown. The expression correlation between TRIP4 and GATA2 and the effect of GATA2 on cervical cancer cell growth were determined respectively by Western Blot, Scratch, Spheroid, and MTT analyses. Pulldown and ChIP experiments were performed to analyze the binding of TRIP4 to the promoter of GATA2. The clinical significance of GATA2 and TRIP4 expression in cervical cancer patients was analyzed by tissue microarray staining. GATA2 was highly expressed in cervical cancer tissues. Knockdown of GATA2 inhibited the growth, metastasis and stemness of cervical cancer cells and sensitized cervical cancer cells to radiation therapy. The inhibitory effect of TRIP4 knockdown on cervical cancer cells was rescued by GATA2 overexpression. Furthermore, TRIP4 could bind to the specific GATA2 promoter region, thereby activating its transcription. Clinical tissue microarray analysis indicated that the expression of TRIP4 and GATA2 was positively correlated, and high expression of both predicted a poor prognosis in cervical cancer patients. Our study demonstrated that GATA2 functions as the key downstream target of TRIP4 to promote cervical cancer progression and effective intervention of TRIP4/GATA2 signaling is expected to be developed as potential cervical cancer therapeutic strategy.

BACKGROUND:Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show initial efficacy in EGFR-mutated lung cancer, but residual disease persists. This study aimed to investigate cluster of differentiation 24 (CD24) as a translational immunotherapeutic target for enhancing third-generation EGFR-TKI efficacy. METHODS:We conducted RNA-sequencing (RNA-seq) on drug-responsive, drug-tolerant persister, and drug-resistant cells to identify therapeutic targets to pair with EGFR-TKIs. For validation, we integrated single-cell RNA-seq data from 29 lung cancer specimens and used single-nucleus RNA-seq and immunohistochemistry on clinical residual tumor samples following TKI therapy (TKI-residual). With CRISPR/Cas9, we studied the effect of CD24 on proliferation and phagocytic clearance during EGFR-TKI treatment. We tested CD24 knockout or ATG-031 (a first-in-class CD24 antibody) with EGFR-TKIs in vitro, xenografts, and spontaneous lung cancer models. To explore mechanisms, we used DNA affinity precipitation, chromatin immunoprecipitation sequencing, and luciferase assays to identify transcription factors regulating CD24. Co-immunoprecipitation combined with mass spectrometry and phosphoproteomics were used to study YIN-YANG-1 (YY1) S247 phosphorylation's expression and function, while kinase inhibitors assessed upstream phosphorylation of YY1 S247 and its regulation of CD24. RESULTS:CD24 expression rose in drug-responsive, -resistant, and -tolerant lung cancer cells and post-EGFR-TKI treatment clinical specimens. This elevation promoted cell proliferation and shielded tumor cells from macrophage-mediated phagocytosis. Genetic depletion of CD24 or treatment with ATG-031 significantly enhanced phagocytosis and tumor eradication in vitro, in xenografts, and in mice harboring EGFRL858R·T790M-driven spontaneous lung tumors. Furthermore, we revealed that YY1 S247 phosphorylation was responsible for the upregulation of CD24 upon EGFR-TKI treatment, facilitating YY1 dimerization and the formation of promoter-enhancer loops that regulate CD24 expression. CONCLUSIONS:CD24 is a promising target in EGFR-mutated lung cancers, potentially enhancing efficacy of third-generation EGFR-TKIs.

Tumor drug resistance emerges from the interaction of two critical factors: tumor cellular heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute essential components of the TME. M2-like TAMs are essential in facilitating tumor metastasis as well as augmenting the drug resistance of tumors. This review encapsulates the mechanisms that M2-like TAMs use to promote tumor drug resistance. We also describe the emerging therapeutic strategies that are currently targeting M2-like TAMs in combination with other antitumor drugs, with some still undergoing clinical trial evaluation. Furthermore, we summarize and analyze various existing approaches for developing novel drugs that target M2-like TAMs to overcome tumor resistance, highlighting how targeting M2-like TAMs can effectively stop tumor growth, metastasis, and overcome tumor drug resistance.

BackgroundProstate cancer is one of the leading causes of cancer-related deaths in men. Its molecular pathogenesis is closely linked to various genetic and epigenetic alterations, including posttranslational modifications like SUMOylation. Identifying biomarkers that predict outcomes and specific therapeutic targets depends on a comprehensive understanding of these processes. With growing interest in SUMOylation as a mechanism affecting prostate cancer-related genes, this study aimed to investigate the central role of SUMOylation in prostate cancer prognostics, focusing on the significance of NOP58.MethodsWe conducted a comprehensive bioinformatics analysis, integrating differential expression analysis, survival analysis, gene set enrichment analysis (GSEA), and single-cell transcriptomic analyses using data from The Cancer Genome Atlas (TCGA). Key genes were identified through intersections of Venn diagrams, Boralta algorithm signatures, and machine learning models. These signaling mechanisms were validated through experimental studies, including immunohistochemical staining and gene ontology analyses.ResultsThe dual-gene molecular subtype analysis with SUMO1, SUMO2, and XPO1 genes revealed significant differences in survival outcomes across molecular subtypes, further emphasizing the potential impact of NOP58 on SUMOylation, a key post-translational modification, in prostate cancer. NOP58 overexpression was strongly associated with shorter overall survival (OS), progression-free interval (PFI), and disease-specific death in prostate cancer patients. Immunohistochemical analysis confirmed that NOP58 was significantly overexpressed in prostate cancer tissues compared to normal tissues. ROC curve analysis demonstrated that NOP58 could distinguish prostate cancer from control samples with high diagnostic accuracy. Gene Ontology analysis, along with GSVA and GSEA, suggested that NOP58 may be involved in cell cycle regulation and DNA repair pathways. Moreover, NOP58 knockdown led to increased BCL2 expression and decreased Ki67 levels, promoting apoptosis and inhibiting cell proliferation. Colony formation assays further showed that NOP58 knockdown inhibited, while its overexpression promoted, colony formation, highlighting the critical role of NOP58 in prostate cancer cell growth and survival. Additionally, NOP58 was linked to drug responses, including Methotrexate, Rapamycin, Sorafenib, and Vorinostat.ConclusionNOP58 is a key regulator of prostate cancer progression through its mediation of the SUMOylation pathway. Its expression level serves as a reliable prognostic biomarker and an actionable therapeutic target, advancing precision medicine for prostate cancer. Targeting NOP58 may enhance therapeutic efficacy and improve outcomes in oncology.

BACKGROUND:As the selective inhibitor of BRAF kinase, vemurafenib exhibits effective antitumor activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after its initial treatment.METHODS:Immunohistochemical staining was performed to detect the expression of iNOS and hTERT, p-p65, Epcam, CD44, PCNA in mice with melanoma xenografts. The proliferation and migration of melanoma cells were detected by MTT, tumorsphere culture, cell cycle, cell apoptosis, AO/EB assay and colony formation, transwell assay and scratch assay in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the iNOS/hTERT signaling pathways were detected by western blot. Nucleus-cytoplasm separation, and immunofluorescence analyses were conducted to explore the location of p50/p65 in melanoma cell lines. Flow cytometry assay were performed to determine the expression of CD44. Pull down assay and ChIP assay were performed to detect the binding ability of p65 at iNOS and hTERT promoters. Additionally, hTERT promoter-driven luciferase plasmids were transfected in to melanoma cells with indicated treatment to determine luciferase activity of hTERT.RESULTS:Melatonin significantly and synergistically enhanced vemurafenib-mediated inhibitions of proliferation, colony formation, migration and invasion and promoted vemurafenib-induced apoptosis, cell cycle arresting and stemness weakening in melanoma cells. Further mechanism study revealed that melatonin enhanced the antitumor effect of vemurafenib by abrogating nucleus translocation of NF-κB p50/p65 and their binding at iNOS and hTERT promoters, thereby suppressing the expression of iNOS and hTERT. The elevated anti-tumor capacity of vemurafenib upon co-treatment with melatonin was also evaluated and confirmed in mice with melanoma xenografts.CONCLUSIONS:Collectively, our results demonstrate melatonin synergizes the antitumor effect of vemurafenib in human melanoma by inhibiting cell proliferation and cancer-stem cell traits via targeting NF-κB/iNOS/hTERT signaling pathway, and suggest the potential of melatonin in antagonizing the toxicity of vemurafenib and augmenting its sensitivities in melanoma treatment.

Glioblastoma (GBM) is highly invasive and lethal. The failure to cure GBM highlights the necessity of developing more effective targeted therapeutic strategies. KIF15 is a motor protein to be involved in cell mitosis promotion, cell structure assembly and cell signal transduction. The precise biological function and the potential upstream regulatory mechanisms of KIF15 in GBM remain elusive. Here, we demonstrated that KIF15 was abnormally up-regulated in GBM and predicted poor prognosis of GBM patients. KIF15 promotes GBM cell proliferation, metastasis and cell cycle progression. REST could bind to KIF15 promoter and transactivate KIF15. Furthermore, REST interacts with P300 and depends on its histone acetyltransferase (HAT) activity to co-regulate KIF15 expression. Both REST and P300 were highly expressed in GBM and predicted poor prognosis of GBM patients alone or in combination with KIF15. The tumorigenic function of KIF15 in GBM was regulated by REST in vitro and in vivo and the combinational treatment of cell cycle inhibitor Palbociclib with P300 HAT inhibitor inhibited GBM xenografts survival more significantly. Our findings indicate that KIF15 promotes GBM progression under the synergistic transactivation of REST and P300. P300/REST/KIF15 signaling axis is expected to be served as a cascade of candidate therapeutic targets in anti-GBM.

As a kind of proteolytic enzyme extracted from earthworms, lumbrokinase has been used as an antithrombotic drug clinically. Nevertheless, its potential in anti-cancer, especially in anti-non-small cell lung cancer (NSCLC), as a single form of treatment or in combination with other therapies, is still poorly understood. In this study, we explored the anti-tumor role and the responsive molecular mechanisms of lumbrokinase in suppressing tumor angiogenesis and chemoresistance development in NSCLC and its clinical potential in combination with bevacizumab and chemotherapeutics. Lumbrokinase was found to inhibit cell proliferation in a concentration-dependent manner and caused metastasis suppression and apoptosis induction to varying degrees in NSCLC cells. Lumbrokinase enhanced the anti-angiogenesis efficiency of bevacizumab by down-regulating BPTF expression, decreasing its anchoring at the VEGF promoter region and subsequent VEGF expression and secretion. Furthermore, lumbrokinase treatment reduced IC50 values of chemotherapeutics and improved their cytotoxicity in parental and chemo-resistant NSCLC cells via inactivating the NF-κB pathway, inhibiting the expression of COX-2 and subsequent secretion of PGE2. LPS-induced NF-κB activation reversed its inhibition on NSCLC cell proliferation and its synergy with chemotherapeutic cytotoxicity, while COX-2 inhibitor celecoxib treatment boosted such effects. Lumbrokinase combined with bevacizumab, paclitaxel, or vincristine inhibited the xenograft growth of NSCLC cells in mice more significantly than a single treatment. In conclusion, lumbrokinase inhibited NSCLC survival and sensitized NSCLC cells to bevacizumab or chemotherapeutics treatment by targeted down-regulation of BPTF/VEGF signaling and inactivation of NF-κB/COX-2 signaling, respectively. The combinational applications of lumbrokinase with bevacizumab or chemotherapeutics are expected to be developed as promising candidate therapeutic strategies to improve the efficacy of the original monotherapy in anti-NSCLC.

Background Lung cancer causes significant mortality, with invasion and metastasis being the main features that cause most cancer deaths. Lymph node metastasis is the primary metastatic route in non-small cell carcinoma (NSCLC) and influences the staging and prognosis of NSCLC. Cumulative studies have reported that Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the progression of various cancers. However, few studies have discussed the function of CEACAM1 in lymphangiogenesis in NSCLC. Here, we examined how CEACAM1 influences lymphangiogenesis in NSCLC. Methods A total of 30 primary squamous cell carcinoma (LUSC) patients diagnosed with LN metastasis were prospectively selected. LUSC tumor tissues, para-cancerous tissues, and positive lymph node tissues were harvested. The expression and subcellular location of CEACAM1, CD31, and LVYE1 in clinical samples were detected by immunohistochemistry. Next, the CEACAM1 and hsa-miR-423-5p expressions were detected by qPCR. The protein expression of lymphangiogenesis-associated proteins and critical cytokines of the NF–κB pathway in HDLECs was detected by Western blot. A tube formation assay was performed to detect the lymphangiogenesis in different groups. The interaction between CEACAM1 and hsa-miR-423-5p was verified using a dual luciferase assay. Results CEACAM1 was found to be a potential gene associated with lung cancer prognosis. It was positively correlated with angiogenesis and lymphangiogenesis. Then, we detected the function of CEACAM1 in lymphangiogenesis and found that CEACAM1 promoted lymphangiogenesis. hsa-miR-423-5p overexpression inhibited lymphangiogenesis via targeting CEACAM1. Finally, we observed that CEACAM1 can activate the NF–κB pathway and, therefore, promote lymphangiogenesis. Conclusion We found that CEACAM1 enhanced lymphangiogenesis in NSCLC via NF-kB activation and was repressed by miR-423-5p. This suggests the value of CEACAM1 as a new therapeutic marker in NSCLC.