Esophageal cancer (EC) is one of the most common causes of cancer-related mortality due in part to challenges in early diagnosis. Biomarker identification is crucial for improved early screening and treatment strategies for patients. Firstly, we employed serum proteomics techniques to screen for potential biomarkers in 15 early-stage EC patients and 5 healthy individuals. Among the differentially expressed proteins, FGL1 emerged as a promising candidate (AUC = 0.974) for early detection of EC. Subsequently, we developed NanoBiT-conjugated dual nanobodies (NBNB) sensors for robust and quantitative signal detection in fetal bovine serum (FBS) in 30 min or less, with a limit of detection (LoD) of 11.38 pM. In a case-control study recruiting 96 EC patients and 99 control samples, testing serum samples with the developed NBNB sensors revealed significantly elevated serum level of FGL1 in all-stage EC patients (AUC = 0.7880) and early-stage EC patients (AUC = 0.8286). Additionally, the combined diagnostic performance of FGL1 and CEA in EC samples is notably enhanced (AUC = 0.8847). These findings propose FGL1 as a novel and promising target for the early-stage EC diagnosis and treatment selection. Furthermore, we applied the assay to patients across six types of cancer, suggesting FGL1 as a potential pan-cancer marker. This study introduces a rapid, easy-to-use, cost-effective, reliable, universal, and high-throughput alternative to meet the growing demand for cancer biomarker testing in both academic and clinical settings.

Gefitinib (GFB) is a well-established EGFR inhibitor used in the treatment of non-small cell lung cancer (NSCLC) that has shown resistance in certain cases of this cancer. In this work, we aimed to enhance GFB's inhibitory activity using alchemical free energy calculations, leading to the design of five new quinazoline derivatives. Among these, compound 8a was the most potent, inhibiting EGFR at 10 µM and showing significant antiproliferative effects at 25 µM. Further optimization identified two new compounds, NCU00 and NCU01, with improved EGFR inhibition and superior cytotoxicity in four NSCLC cell lines compared to GFB. Molecular dynamics simulations revealed crucial interactions that contribute to the enhanced inhibitory activity of NCU00 and NCU01. Toxicological assessments in mice showed no adverse effects on kidney or liver function, and NCU01 exhibited no developmental toxicity in zebrafish embryos. This study highlights the effectiveness of alchemical free energy methods in optimizing quinazoline-bearing EGFR inhibitors.

Emerging evidence from recent studies demonstrates that the FGL1/LAG-3 interaction axis plays a crucial role in mediating tumor immune evasion mechanisms, particularly through the suppression of T lymphocyte effector functions. However, the role of FGL1 in prostate cancer (PCa) remains unclear. Data was downloaded from The Cancer Genome Atlas (TCGA) database, and subjected to differential expression analysis. Single gene differential analysis to determine the correlation between FGL1 and DNAJC12 expression levels in prostate cancer. The expression of FGL1 was silenced by siRNA in PC3 prostate cancer cells. Lentiviruses infected DU145 to overexpress FGL1. Cell proliferation, apoptosis and EMT-related markers were detected in vitro. Animal experiments further confirmed the effect of FGL1 on prostate cancer. Up-regulated gene FGL1 was identified as the selected gene in this study among 3011 Differentially expressed genes. FGL1 had the highest positive relation with DNAJC12. The OS of PCa patients with high expression of FGL1 was significantly shorter. After silencing FGL1, PC3 cell proliferation was inhibited by 0.58-fold, while apoptosis increased by 16%, and the expression of cleaved-caspase-3 increased, while the expression of DNAJC12 and BCL-2 decreased. After overexpression of FGL1, the number of DU145 cells increased by 2.05-fold, the expression of cleaved-caspase-3 was inhibited, E-cadherin expression decreased, while N-cadherin and Vimentin expression increased. Tumor growth was inhibited, and the expression of FN1, n-cadherin, Vimentin and β-catenin decreased, while the expression of E-cadherin increased after silencing FGL1. Silencing FGL1 promotes prostate cancer cell apoptosis and inhibits EMT progression. FGL1 may be an independent prognostic marker and therapeutic target in PCa.

Gefitinib, a first-line tyrosine kinase inhibitor (TKI) target to non-small cell lung cancer (NSCLC) treatment, is known to cause hepatotoxicity, which seriously limiting its therapeutic application. This study investigated the underlying mechanisms of gefitinib-induced liver injury and the protective effects of glycyrrhizic acid (GL) in mice and AML12 cells. Sixty mice were randomly divided into six groups: control, gefitinib, glutathione (200 mg/kg), and three doses of GL (50, 100, and 200 mg/kg). Liver injury was induced in mice through daily oral administration of gefitinib (400 mg/kg) for 16 days, with hepatotoxicity was assessed through serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, and hepatic histopathology. Hepatic mRNA profiles were analyzed using RNA sequencing, with differentially expressed genes (DEGs) confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Finally, the effect of GL on the anticancer efficacy of gefitinib was assessed in A549 and Lewis lung carcinoma (LLC) lung cancer cells, as well as in a urethane-induced lung cancer mouse model. GL treatment significantly reduced liver index and serum ALT and AST levels, while also improving hepatic histopathology. Transcriptomic analysis identified 114 DEGs linked to the p53 pathway and cell cycle regulation. Further study indicated that GL inhibited the expression of p53 and p21, thereby upregulated Cyclin D1 expression, thereby alleviating gefitinib-induced cell cycle arrest without impairing its anticancer activity in vivo and in vitro. These findings highlight the potential of GL as a safe adjunct therapy, effectively mitigating gefitinib-induced hepatotoxicity while preserving its anticancer efficacy.

Fibrinogen-like protein 1 (FGL1), a liver-secreted protein involved in proliferation and metabolism, and lymphocyte activation gene 3 (LAG3), an immune checkpoint receptor expressed on the surfaces of various activated immune cells, play critical roles in tumor immunology. Numerous studies have confirmed that FGL1 acts as a ligand for LAG3 and mediates immune evasion by tumor cells. This review aims to provide a comprehensive summary of the research progress in FGL1/LAG3 in terms of its expression, role in the tumor microenvironment, and clinical application. The expression and regulation of FGL1/LAG3 are influenced by multiple cytokines and signaling pathways. In the tumor microenvironment, FGL1/LAG3 modulates tumor cell proliferation, invasion, and migration through mechanisms such as epithelial-mesenchymal transition, gene methylation, oxygen metabolism, and lipid metabolism. FGL1/LAG3 can serve as a prognostic biomarker, independently or in combination with PD-L1/PD-1, and can be targeted using monoclonal antibodies, bi-specific antibodies, and dual-targeted vaccines to restore the proliferation and activation potential of T cells. Additionally, FGL1/LAG3 has demonstrated therapeutic potential when combined with targeted therapies, radiotherapy, traditional Chinese medicine, and adoptive cell therapy. Overall, FGL1/LAG3 plays a pivotal role in cancer initiation, progression, diagnosis, treatment, and prognosis.

The objective of the present study was to elucidate the mechanism by which glycyrrhizin enhances the antitumor activity of cisplatin in non-small cell lung cancer. Initially, A549 cells were treated with different concentrations of glycyrrhizin (0.25-8 mM) or cisplatin (10-160 µM) for 48 h to investigate the effect of glycyrrhizin combined with cisplatin on A549 cells in vitro. Subsequently, A549 cells were divided into control (untreated), CP (20 µM cisplatin), GL (2 mM glycyrrhizin) and CP + GL (20 µM cisplatin + 2 mM glycyrrhizin) groups to elucidate the underlying mechanism of glycyrrhizin. After 48 h incubation, the viability and colony-forming ability of the cells were assessed using MTT and colony formation assays. Apoptosis levels and cell cycle progression were analyzed using flow cytometry and western blotting was used to evaluate apoptosis- and cell cycle-related proteins. Additionally, comet assays and western blotting were used to evaluate DNA damage and relevant proteins. The results demonstrated both glycyrrhizin and cisplatin individually reduced A549 cell viability in a concentration-dependent manner. Cisplatin demonstrated a lower half-maximal inhibitory concentration (IC50) at higher glycyrrhizin concentrations, with an IC50 value of ~35 µM with 2 mM glycyrrhizin. Furthermore, the combined treatment of glycyrrhizin and cisplatin synergistically reduced cell colony-forming ability, induced apoptosis and arrested the cell cycle at the G2 phase, showing greater efficacy when compared with either treatment individually. In addition, western blotting analysis demonstrated that, in comparison with treatment with cisplatin or glycyrrhizin alone, the combined treatment markedly increased the protein expression levels of B-cell lymphoma 2-associated X protein, cleaved-caspase-3/caspase-3, γH2AX, phosphorylated-checkpoint kinase 1 and phosphorylated-p53/p53, while notably reducing the protein levels of B-cell lymphoma 2, cyclin D1, cyclin-dependent kinase 2 and cyclin-dependent kinase 4. The findings of the present study indicate that glycyrrhizin enhances the antitumor efficacy of cisplatin in non-small cell lung cancer cells by modulating DNA damage and apoptosis.

Microsatellite instability (MSI) is a phenotype characterized by changes in the sequence length of microsatellites in tumor cells and is closely linked to tumorigenesis and prognosis. Immune checkpoint inhibitors have shown good therapeutic effects in gastric cancer (GC) with MSI-high (MSI-H). However, the role of the novel immune checkpoint fibrinogen-like protein 1 (FGL1) in GC treatment has not been fully investigated. FGL1 expression in GC tissues and the difference in FGL1 immune infiltration between MSI/ microsatellite stability (MSS) patients were analyzed by bioinformatics and were verified in clinical samples. Xenograft models of MSS and MSI GC were constructed in human immune reconstitution mice, and FGL1 expression in tumors was detected. Immunofluorescence and immunohistochemistry were used to assay the infiltration of immune cells in the two types of mice. Cytotoxicity and chemotaxis tests were used to detect the toxicity and chemotaxis of CD8+T cells to GC cells, respectively. The cytokine content was detected by enzyme-linked immunosorbent assay. The therapeutic effects of FGL1 antibody on different types of GC were analyzed by xenograft mouse models. FGL1 exhibited significantly higher expression in GC, and its expression and immune cell infiltration levels were significantly higher in MSI GC than in MSS GC. CD8+T cells were significantly more effective in killing and chemotaxis of MSI GC cells than MSS GC cells. The FGL1 antibody was more effective in treating MSI GC.The novel immunosuppressor FGL1 antibody exerts a good therapeutic influence on MSI GC. These findings provide a basis for the development of drugs targeting FGL1 for MSI GC treatment.

Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis. The trifluoromethyl quinazoline compound KZL-201 was designed and synthesized, and its inhibitory effect on the progression of OS cells was investigated. The aim of this study was to investigate the underlying mechanism of action of KZL-201 in OS using a combination of bioinformatics analysis, molecular biology, cytology, and zoology. The in vitro experiments showed that KZL-201 inhibited OS cell proliferation, invasion, and migration; KZL-201 induced apoptosis and arrested the cell cycle at the G2/M phase. The results of molecular docking, the cellular thermal shift assay, and gene silencing experiments showed that KZL-201 had a strong affinity for MMP13. KZL-201 inhibited the progression of 143B cells by regulating the TGF-β1/Smad2/3 pathway. Thus, MMP13 is an important target gene of KZL-201 in inhibiting 143B cell progression. The in vivo experiments showed that KZL-201 inhibited the growth of OS tissues and the expression of MMP13 in OS tissues. In summary, KZL-201 targeted MMP13 and inhibited its expression, consequently suppressing the progression of OS by regulating the TGF-β1/Smad2/3 pathway.

Background/Objectives: Predicting the behavior of clear cell renal cell carcinoma (ccRCC) is challenging using standard-of-care histopathologic examination. Indeed, pathologic RCC tumor grading, based on nuclear morphology, performs poorly in predicting outcomes of patients with International Society of Urological Pathology/World Health Organization grade 2 and 3 tumors, which account for most ccRCCs. Methods: We applied spatial point process modeling of H&E-stained images of patients with grade 2 and grade 3 ccRCCs (n = 72) to find optimum separation into two groups. Results: One group was associated with greater spatial randomness and clinical metastasis (p < 0.01). Notably, spatial analysis outperformed standard pathologic grading in predicting clinical metastasis. Moreover, cell-to-cell interaction distances in the metastasis-associated group were significantly greater than those in the other patient group and were also greater than expected by the random distribution of cells. Differential gene expression between the two spatially defined groups of patients revealed a matrisome signature, consistent with the extracellular matrix's crucial role in tumor invasion. The top differentially expressed genes (with a fold change > 3) stratified a larger, multi-institutional cohort of 352 ccRCC patients from The Cancer Genome Atlas into groups with significant differences in survival and TNM disease stage. Conclusions: Our results suggest that the spatial distribution of ccRCC tumor cells can be extracted from H&E-stained images and that it is associated with metastasis and with extracellular matrix genes that are presumably driving these tumors' aggressive behavior.

Immune escape is the major reason for immunotherapy failure in stomach adenocarcinoma (STAD). We tried to reveal the underlying mechanism of FGL1 influencing STAD in this study. Bioinformatics analyses were conducted to analyze the expression of FGL1, the signaling pathways affected by FGL1, and the relation between FGL1 and immune cell infiltration. Quantitative real-time PCR (qRT-PCR), cell counting kit-8 assay, colony formation assay, flow cytometry and Transwell assay were adopted to analyze FGL1 expression, cell viability, cell proliferation, cell apoptosis, and cell invasion, respectively. Enzyme-linked immunosorbent assay, lactate dehydrogenase method, qRT-PCR and Western blot were adopted to reveal proinflammatory cytokine expression, cytotoxicity and mRNA and protein expression of the Notch signaling-related genes, respectively, after co-culture of STAD cells and CD8+T cells. Nude mice experiment was conducted to validate the results obtained above. FGL1 expressed highly in STAD and could activate the Notch signaling pathway, and it was negatively correlated with CD8+T cell infiltration. Cell experiments confirmed that high expression of FGL1 facilitated proliferation and hindered apoptosis of STAD cells. Knockdown of FGL1 could facilitate expression of pro-inflammatory factors and the cytotoxicity of CD8+T cells in co-culture system of STAD and CD8+ T cells. Knockdown of FGL1 could suppress the expression of the Notch signaling pathway-related genes, and the addition of Notch inhibitor proved that FGL1 promoted immune escape via the Notch signaling pathway. This study investigated the influence of FGL1 on STAD immune escape and demonstrated that FGL1 inhibited CD8+ T cell activation by activating the Notch signaling pathway and thus promoted tumor immune escape in STAD, providing a new potential diagnostic marker and therapeutic target for the immunotherapy of STAD patients.

Lung cancer remains one of the most common malignant cancers worldwide, and its survival rate is extremely low. Chemotherapy, the mainstay of lung cancer treatment, is not as effective as it could be due to the development of cellular resistance. The molecular mechanisms of drug resistance in lung cancer remain to be elucidated. Accumulating evidence suggests that ceRNAs are involved in various carcinogenesis and development. CeRNA is a transcript that regulates each other through competition with miRNA. However, the relationship between ceRNAs and chemoresistance in lung cancer remains unclear. In this narrative review, we provided a summary of treatment approaches that focus on ceRNA networks to overcome drug resistance.

Isoquercitrin possesses anti-tumor activity in several types of cancers, however, its effects and underlying mechanisms on lung cancer have not been reported. Human lung cancer cell lines as well as normal lung epithelial BEAS-2B cells were treated with isoquercitrin. The influences of isoquercitrin in vitro were evaluated by determining cell viability, apoptosis, pyroptosis, and ferroptosis. Additionally, A549 tumor-bearing mice were generated to explore the anti-cancer effect of isoquercitrin in vivo. We found that isoquercitrin dose-dependently reduced lung cancer cells' viability, with no toxicity against BEAS-2B cells. Isoquercitrin at 40 μM and 80 μM was used in vitro. Isoquercitrin increased apoptosis, elevated NLRP3 inflammasome activation-mediated pyroptosis, and promoted ferroptosis in lung cancer cells. NLRP3 knockdown and caspase-1 selective inhibitor VX-765 attenuated isoquercitrin-induced pyroptosis and ferroptosis, but not apoptosis. Furthermore, isoquercitrin accelerated ROS generation, while ROS inhibitor N-acetylcysteine abrogated isoquercitrin-induced apoptosis, NLRP3 related-pyroptosis and ferroptosis. In vivo, isoquercitrin (1 mg/kg and 5 mg/kg) inhibited tumor growth, increased apoptosis, NLRP3-related pyroptosis, ferroptosis and ROS generation in tumors. Taken together, isoquercitrin inhibits lung cancer growth by triggering ROS/NLRP3-mediated pyroptosis and ferroptosis, with ROS also directly inducing apoptosis. This suggests that isoquercitrin might be a potential therapeutic agent for lung cancer.

Treatment based on immune checkpoint blockade has revolutionized cancer therapy. Despite the remarkable success achieved and the preclinical development of multiple checkpoint inhibitors targeting other checkpoints, only antibodies targeting the PD-1/PD-L1 axis and CTLA-4 have been approved for patient treatment, especially in solid tumors. Currently, with the approval of relatlimab, a LAG-3 blocking antibody, a third player, has been used in the fight against cancer. The endorsement of relatlimab marks a significant milestone in cancer immunotherapy, opening new avenues for combination therapies and enhancing treatment outcomes. However, the complex biology of LAG-3 may hinder its full development as a therapeutic alternative. In this review, we provide in-depth insight into the biology of LAG-3 and its current and future development in cancer treatment.

EGFR-TKIs have been used as frontline treatment in patients with advanced non-small cell lung cancer (NSCLC) suffering from the EGFR mutation. Gefitinib, the first-generation EGFR-TKI, has greatly improved survival rates in lung cancer patients, whereas acquired gefitinib resistance is still a critical issue that needs to be overcome. In our research, high expression levels of CIB2 were found in gefitinib-resistant lung cancer cells. CIB2 knockout rendered gefitinib-resistant cells more sensitive to gefitinib, and overexpression of CIB2 in parental cells was sufficient to induce more resistance to gefitinib. Inhibition of CIB2 in gefitinib-resistant lung cancer cells significantly induced cell apoptosis. To clarify the major molecular mechanism by which CIB2 increases gefitinib resistance, we demonstrated that raised CIB2 in lung cancer cells promoted epithelial-to-mesenchymal transition (EMT) through upregulation of ZEB1. Moreover, FOSL1 transcriptionally regulated CIB2 expression. Finally, CIB2 rendered tumors resistant to gefitinib treatment in vivo. Our results explored a new mechanism: upregulated CIB2 promoted EMT through ZEB1 to regulate gefitinib resistance, which could be a candidate therapeutic target for overcoming acquired resistance to EGFR-TKIs in NSCLC patients.

Programmed cell death (PCD) is a fundamental biological process for maintaining cellular equilibrium and regulating development, health, and disease across all living organisms. Among the various types of PCD, apoptosis plays a pivotal role in numerous diseases, notably cancer. Cancer cells frequently develop mechanisms to evade apoptosis, increasing resistance to standard chemotherapy treatments. This resistance has prompted extensive research into alternative mechanisms of programmed cell death. One such pathway is oncosis, characterized by significant energy consumption, cell swelling, dilation of the endoplasmic reticulum, mitochondrial swelling, and nuclear chromatin aggregation. Recent research suggests that oncosis can impact conditions such as chemotherapeutic cardiotoxicity, myocardial ischemic injury, stroke, and cancer, mediated by specific oncosis-related proteins. In this review, we provide a detailed examination of the morphological and molecular features of oncosis and discuss various natural or small molecule compounds that can induce this type of cell death. Additionally, we summarize the current understanding of the molecular mechanisms underlying oncosis and its role in both normal physiology and pathological conditions. These insights aim to illuminate future research directions and propose innovative strategies for leveraging oncosis as a therapeutic tool against human diseases and cancer resistance.

Traditional therapeutic approaches such as chemotherapy and radiation therapy have burdened cancer patients with onerous physical and psychological challenges. Encouragingly, the landscape of tumor treatment has undergone a comprehensive and remarkable transformation. Emerging as fervently pursued modalities are small molecule targeted agents, antibody-drug conjugates (ADCs), cell-based therapies, and gene therapy. These cutting-edge treatment modalities not only afford personalized and precise tumor targeting, but also provide patients with enhanced therapeutic comfort and the potential to impede disease progression. Nonetheless, it is acknowledged that these therapeutic strategies still harbour untapped potential for further advancement. Gaining a comprehensive understanding of the merits and limitations of these treatment modalities holds the promise of offering novel perspectives for clinical practice and foundational research endeavours. In this review, we discussed the different treatment modalities, including small molecule targeted drugs, peptide drugs, antibody drugs, cell therapy, and gene therapy. It will provide a detailed explanation of each method, addressing their status of development, clinical challenges, and potential solutions. The aim is to assist clinicians and researchers in gaining a deeper understanding of these diverse treatment options, enabling them to carry out effective treatment and advance their research more efficiently.

Human intervertebral disk degeneration (IVDD) is a sophisticated degenerative pathological process. A key cause of IVDD progression is nucleus pulposus cell (NPC) degeneration, which contributes to excessive endoplasmic reticulum stress in the intervertebral disk. However, the mechanisms underlying IVDD and NPC degeneration remain unclear.

We used interleukin (IL)-1β stimulation to establish an NPC-degenerated IVDD model and investigated whether human urine-derived stem cell (USC) exosomes could prevent IL-1β-induced NPC degeneration using western blotting, quantitative real-time polymerase chain reaction, flow cytometry, and transcriptome sequencing techniques.

We successfully extracted and identified USCs and exosomes from human urine. IL-1β substantially downregulated NPC viability and induced NPC degeneration while modulating the expression of SOX-9, collagen II, and aggrecan. Exosomes from USCs could rescue IL-1β-induced NPC degeneration and restore the expression levels of SOX-9, collagen II, and aggrecan.

USC-derived exosomes can prevent NPCs from degeneration following IL-1β stimulation. This finding can aid the development of a potential treatment strategy for IVDD.

Fibrinogen-like protein 1 (FGL1) is a proliferation- and metabolism-related factor secreted by the liver that is aberrantly expressed and functionally abnormal in human malignancies. However, the role of FGL1 in head and neck squamous cell carcinoma (HNSCC) remains unknown. We analysed FGL1 expression in HNSCC and its impact on patient survival using the TCGA database. The role of FGL1 in HNSCC cells was investigated by Cell Counting Kit-8, colony formation, and Transwell assays. In addition, we conducted in vivo experiments to assess the effect of FGL1 knockdown on tumour growth. We found that FGL1 was highly expressed in HNSCC and correlated with a poor prognosis. Downregulation of FGL1 expression inhibited the proliferation and invasion of HNSCC cells. Furthermore, mechanistic analysis revealed that FGL1 induced an epithelial-mesenchymal transition (EMT) phenotype and, thus, the malignant progression of HNSCC cells. Finally, xenograft models showed that FGL1 knockdown significantly inhibited EMT in HNSCC in vivo. Our study revealed that FGL1, an oncogene, promotes the malignant progression of HNSCC, providing new perspective on and potential therapeutic target for the treatment of HNSCC.

Liver disease is a complex group of diseases with high morbidity and mortality rates, emerging as a major global health concern. Recent studies have highlighted the involvement of fibrinogen-like proteins, specifically fibrinogen-like protein 1 (FGL1) and fibrinogen-like protein 2 (FGL2), in the regulation of various liver diseases. FGL1 plays a crucial role in promoting hepatocyte growth, regulating lipid metabolism, and influencing the tumor microenvironment (TME), contributing significantly to liver repair, non-alcoholic fatty liver disease (NAFLD), and liver cancer. On the other hand, FGL2 is a multifunctional protein known for its role in modulating prothrombin activity and inducing immune tolerance, impacting viral hepatitis, liver fibrosis, hepatocellular carcinoma (HCC), and liver transplantation. Understanding the functions and mechanisms of fibrinogen-like proteins is essential for the development of effective therapeutic approaches for liver diseases. Additionally, FGL1 has demonstrated potential as a disease biomarker in radiation and drug-induced liver injury as well as HCC, while FGL2 shows promise as a biomarker in viral hepatitis and liver transplantation. The expression levels of these molecules offer exciting prospects for disease assessment. This review provides an overview of the structure and roles of FGL1 and FGL2 in different liver conditions, emphasizing the intricate molecular regulatory processes and advancements in targeted therapies. Furthermore, it explores the potential benefits and challenges of targeting FGL1 and FGL2 for liver disease treatment and the prospects of fibrinogen-like proteins as biomarkers for liver disease, offering insights for future research in this field.

While radiation therapy remains pivotal in esophageal squamous cell carcinoma (ESCC) treatment, the perplexing phenomenon of post-radiation metastasis presents a formidable clinical challenge. This study investigates the role of fibrinogen-like protein 1 (FGL1) in driving ESCC metastasis following radiation exposure.

FGL1 expression in post-radiation ESCC cells was meticulously examined using qRT-PCR, western blotting, and immunofluorescence. The impact of FGL1 on ESCC cell invasion and migration was assessed through Transwell and wound healing assays. In vivo, the metastatic potential of ESCC in response to FGL1 was scrutinized using nude mice models. Comprehensive RNA sequencing and functional experiments elucidated the intricate mechanism associated with FGL1.

Radiation induced upregulation of FGL1 in ESCC cells through FOXO4, intensifying ESCC cell invasion and migration. Targeted knockdown of FGL1 effectively alleviated these characteristics both in vitro and in vivo. FGL1 depletion concurrently suppressed IMPDH1 expression. Rescue experiments underscored that IMPDH1 knockdown robustly reversed the pro-invasive effects induced by FGL1 in ESCC cells. ESCC tissues exhibited heightened IMPDH1 mRNA levels, demonstrating a correlation with patient survival.

Radiation-induced upregulation of FGL1 propels ESCC metastasis through IMPDH1, proposing a potential therapeutic target to mitigate post-radiotherapy metastasis in ESCC patients.

Exportin-1 (XPO1), a crucial protein regulating nuclear-cytoplasmic transport, is frequently overexpressed in various cancers, driving tumor progression and drug resistance. This makes XPO1 an attractive therapeutic target. Over the past few decades, the number of available nuclear export-selective inhibitors has been increasing. Only KPT-330 (selinexor) has been successfully used for treating haematological malignancies, and KPT-8602 (eltanexor) has been used for treating haematologic tumours in clinical trials. However, the use of nuclear export-selective inhibitors for the inhibition of XPO1 expression has yet to be thoroughly investigated in clinical studies and therapeutic outcomes for solid tumours.

We collected numerous literatures to explain the efficacy of XPO1 Inhibitors in preclinical and clinical studies of a wide range of solid tumours.

In this review, we focus on the nuclear export function of XPO1 and results from clinical trials of its inhibitors in solid malignant tumours. We summarized the mechanism of action and therapeutic potential of XPO1 inhibitors, as well as adverse effects and response biomarkers.

XPO1 inhibition has emerged as a promising therapeutic strategy in the fight against cancer, offering a novel approach to targeting tumorigenic processes and overcoming drug resistance. SINE compounds have demonstrated efficacy in a wide range of solid tumours, and ongoing research is focused on optimizing their use, identifying response biomarkers, and developing effective combination therapies.

Exportin-1 (XPO1) plays a critical role in mediating nucleocytoplasmic transport and cell cycle. XPO1 dysfunction promotes tumourigenesis and drug resistance within solid tumours. The therapeutic potential and ongoing researches on XPO1 inhibitors in the treatment of solid tumours. Additional researches are essential to address safety concerns and identify biomarkers for predicting patient response to XPO1 inhibitors.

Partial hepatectomy is a first-line treatment for hepatocellular carcinoma. Within 2 weeks following partial hepatectomy, specific molecular pathways are activated to promote liver regeneration. Nevertheless, residual microtumors may also exploit these pathways to reappear and metastasize. Therapeutically targeting molecules that are differentially regulated between normal cells and malignancies, such as fibrinogen-like protein 1 (FGL1), appears to be an effective approach. The potential functions of FGL1 in both regenerative and malignant cells are discussed within the ambit of this review. While FGL1 is normally elevated in regenerative hepatocytes, it is normally downregulated in malignant cells. Hepatectomy does indeed upregulate FGL1 by increasing the release of transcription factors that promote FGL1, including HNF-1α and STAT3, and inflammatory effectors, such as TGF-β and IL6. This, in turn, stimulates certain proliferative pathways, including EGFR/Src/ERK. Hepatectomy alters the phase transition of highly differentiated hepatocytes from G0 to G1, thereby transforming susceptible cells into cancerous ones. Activation of the PI3K/Akt/mTOR pathway by FGL1 allele loss on chromosome 8, a tumor suppressor area, may also cause hepatocellular carcinoma. Interestingly, FGL1 is specifically expressed in the liver via HNF-1α histone acetylase activity, which triggers lipid metabolic reprogramming in malignancies. FGL1 might also be involved in other carcinogenesis processes such as hypoxia, epithelial-mesenchymal transition, immunosuppression, and sorafenib-mediated drug resistance. This study highlights a research gap in these disciplines and the necessity for additional research on FGL1 function in the described processes.

Forkhead box M1 (FOXM1) functions as a transcription factor and is consistently overexpressed in various cancers, including non-small-cell lung-, breast-, cervical-, and colorectal cancer. Its overexpression is associated with poor prognosis in patients with non-small-cell lung cancer, although the detailed mechanisms by which FOXM1 promotes the development of non-small-cell lung cancer remain unclear.

The mechanism of FOXM1 in migration, invasion, apoptosis, and viability of lung cancer cells was investigated.

Transwell assay, scratch test, and flow cytometry were employed to study the effects of FOXM1 on migration, invasion, and apoptosis in A549 cells. A quantitative polymerase chain reaction was used to determine the impact of FOXM1 on miR-509-5p expression in A549 cells. Dual-luciferase reporter gene assay and chromatin immunoprecipitation were adopted to investigate the molecular mechanisms of FOXM1 on miR-509-5p expression.

FDI-6 (a FOXM1 inhibitor) reduced the protein abundance of FOXM1, thereby increasing the expression of miR-509-5p in A549 cells. Moreover, FDI-6 treatment significantly reduced migration, invasion, and viability of A549 cells while promoting cell apoptosis. Furthermore, miR-509-5p inhibitor obviously alleviated the biological effects of FDI-6 on A549 cells, suggesting that FOXM1 primarily exerted its cancer promoting effect by regulating miR-509-5p. Mechanistically, FOXM1 directly bound to the miR-509-5p promoter to inhibit miR-509-5p expression.

FOXM1 directly binds to the promoter region of miR-509-5p to form a negative feedback loop, thereby inhibiting miR-509-5p expression and promoting the development of non-small-cell lung cancer. This study is expected to complement research on the pathogenesis of non-small-cell lung cancer and promote the development of novel therapeutic targets for this disease.

Gefitinib is one of the most extensively utilized epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for treating advanced lung adenocarcinoma (LUAD) patients harboring EGFR mutation. However, the emergence of drug resistance significantly compromised the clinical efficacy of EGFR-TKIs. Gaining further insights into the molecular mechanisms underlying gefitinib resistance holds promise for developing novel strategies to overcome the resistance and improve the prognosis in LUAD patients. Here, we identified that the inhibitory efficacy of gefitinib on EGFR-mutated LUAD cells was partially dependent on the induction of ferroptosis, and ferroptosis protection resulted in gefitinib resistance. Among the ferroptosis suppressors, aldo-keto reductase family 1 member C1 (AKR1C1) exhibited significant upregulation in gefitinib-resistant strains of LUAD cells and predicted poor progression-free survival (PFS) and overall survival (OS) of LUAD patients who received first-generation EGFR-TKI treatment. Knockdown of AKR1C1 partially reversed drug resistance by re-sensitizing the LUAD cells to gefitinib-mediated ferroptosis. The decreased expression of miR-338-3p contributed to the aberrant upregulation of AKR1C1 in gefitinib-resistant LUAD cells. Furthermore, upregulated long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) sponged miR-338-3p to neutralize its suppression on AKR1C1. Dual-luciferase reporter assay and miRNA rescue experiment confirmed the NEAT1_1/miR-338-3p/AKR1C1 axis in EGFR-mutated LUAD cells. Gain- and loss-of-function assays demonstrated that the NEAT1_1/miR-338-3p/AKR1C1 axis promoted gefitinib resistance, proliferation, migration, and invasion in LUAD cells. This study reveals the effects of NEAT1_1/miR-338-3p/AKR1C1 axis-mediated ferroptosis defence in gefitinib resistance in LUAD. Thus, targeting NEAT1_1/miR-338-3p/AKR1C1 axis might be a novel strategy for overcoming gefitinib resistance in LUAD harboring EGFR mutation.

Fibrinogen-like protein-1 (FGL1) is confirmed a major ligand of lymphocyte activation gene-3 which could inhibit antigen-mediated T-cell response and evade immune supervision. Although hepatocytes secrete large amounts of FGL1, its high expression also be detected in solid tumors such as lung cancer, leading to a poor efficacy of immune checkpoint inhibitors therapy. Here we reported that FGL1 was overexpressed in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma. However, FGL1 in tissue and plasma can only distinguish LUAD patients from healthy donors and cannot correlate with clinical Tumor Node Metastasis (TNM) stage. Using lung cancer cell lines, we confirmed that FGL1 can be detected on extracellular vesicles (EVs) and we established a method using flow cytometry to detect FGL1 on the surface of EVs, which revealed that FGL1 could be secreted via EVs. Both animal model and clinical samples proved that plasma FGL1 in EVs would increase when the tumor was loaded. The level of FGL1 in plasma EVs was correlated with clinical TNM stage and tumor size, and a higher level indicated non-responsiveness to anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy. Its effect on tumor progression and immune evasion may be achieved by impairing the killing and proliferating capacities of CD8+ T cells. Our result demonstrates that FGL1 levels in plasma EVs, but not total plasma FGL1, could be a promising biomarker that plays an important role in predicting anti-PD-L1 immune therapy in LUAD and suggests a new strategy in LUAD immunotherapy.

Anlotinib is an effective targeted therapy for advanced non-small-cell lung cancer (NSCLC) and has been found to mediate chemoresistance in many cancers. However, the underlying molecular mechanism of anlotinib mediates cisplatin (DDP) resistance in NSCLC remains unclear.

Cell viability was assessed by the cell counting kit 8 assay. Cell proliferation, migration, and invasion were determined using the colony formation assay and transwell assay. The mRNA expression levels of mesenchymal-epithelial transition factor (MET) and myeloid cell leukemia-1 (MCL-1) were measured by quantitative real-time PCR. Protein expression levels of MET, MCL-1, and STAT3/Akt pathway-related markers were examined using western blot analysis.

Our data showed that anlotinib inhibited the DDP resistance of NSCLC cells by regulating cell proliferation and metastasis. Moreover, MET and MCL-1 expression could be decreased by anlotinib treatment. Silencing of MET suppressed the activity of the STAT3/Akt pathway and MCL-1 expression. Furthermore, MET overexpression reversed the inhibitory effect of anlotinib on the DDP resistance of NSCLC cells, and this effect could be eliminated by MCL-1 knockdown or ACT001 (an inhibitor for STAT3/Akt pathway).

Our results confirmed that anlotinib inhibited DDP resistance in NSCLC cells, which might decrease MCL-1 expression via mediating the MET/STAT3/Akt pathway.

α-Conotoxin ImI is a selective antagonist of alpha7 nicotinic acetylcholine receptor (α7 nAChR) that is involved in cancer development. Human alpha fetoprotein domain 3 (AFP3) is a prototype of anticancer agents. In an effort to design drugs for anticancer treatments, we fused the ImI peptide to AFP3 as a fusion protein for testing. The fusion protein (ImI-AFP3) was highly expressed in the insect Bac-to-Bac system. The purified fusion protein was found to have improved anticancer activity and synergized with the drug gefitinib to inhibit the growth and migration of A549 and NCI-H1299 lung cancer cells. Our data have demonstrated that the recombinant protein ImI-AFP3 is a promising candidate for drug development to suppress lung cancer cell growth, especially to suppress hepatoid adenocarcinoma of the lung (HAL) cell growth.

Bladder cancer is a prevalent malignancy affecting the urinary system, which presents a significant global health concern. Although there are many treatments for bladder cancer, identifying more effective drugs and methods remains an urgent problem. As a pivotal component of contemporary medical practice, traditional Chinese medicine (TCM) assumes a crucial role in the realm of anti-tumor therapy, especially with the identification of active ingredients and successful exploration of pharmacological effects. Febrifugine, identified as a quinazoline-type alkaloid compound extracted from the Cytidiaceae family plant Huangchangshan, exhibits heightened sensitivity to bladder cancer cells in comparison to control cells (non-cancer cells) group. The proliferation growth of bladder cancer cells T24 and SW780 was effectively inhibited by Febrifugine, and the IC50 was 0.02 and 0.018 μM respectively. Febrifugine inhibits cell proliferation by suppressing DNA synthesis and induces cell death by reducing steroidogenesis and promoting apoptosis. Combined with transcriptome analysis, Febrifugine was found to downregulate low density lipoprotein receptor-associated protein, lanosterol synthase, cholesterol biosynthesis second rate-limiting enzyme, 7-dehydrocholesterol reductase, flavin adenine dinucleotide dependent oxidoreductase and other factors to inhibit the production of intracellular steroids in bladder cancer T24 cells. The results of animal experiments showed that Febrifugine could inhibit tumor growth. In summary, the effect of Febrifugine on bladder cancer is mainly through reducing steroid production and apoptosis. Therefore, this study contributes to the elucidation of Febrifugine's potential as an inhibitor of bladder cancer and establishes a solid foundation for the future development of novel therapeutic agents targeting bladder cancer.

Overexpression of the epidermal growth factor receptor (EGFR) has been implicated in the development of non-small-cell lung cancer (NSCLC). Thus, EGFR is an effective drug target for the treatment of NSCLC, and developing fourth-generation EGFR inhibitors to overcome the resistance mediated by T790M/C797S mutations are currently under investigation. In this study, based on the binding model between Angew2017-7634-1 and EGFRT790M/C797S , several series of 2-phenyl-4-aminopyrimidine derivatives were designed and synthesized. The bioactivity of these compounds was evaluated and it is suggested that compound A23 could effectively inhibit the proliferation of Ba/F3-EGFRDel19/T790M/C797S and H1975-EGFRL858R/T790M cells, with an IC50 of 0.22 ± 0.07 and 0.52 ± 0.03 μM, respectively. Meanwhile, the kinase activity of A23 against EGFRL858R/T790M and EGFRDel19/T790M/C797S was also evaluated, with an IC50 of 0.33 and 0.133 μM, respectively. Moreover, compound A23 was further evaluated in the H1975 xenograft models with significant in vivo tumor growth inhibitions of 25.5%, which means that A23 could effectively inhibit the growth of tumor cells and promote the death of tumor cells. As a result, A23 could be identified as a novel potential EGFRDel19/T790M/C797S inhibitor.

Fuzheng Kang-Ai (FZKA) decoction is mainly composed of 12 components with different types of herbs. In the last decade, FZKA has been used as an adjuvant treatment for lung cancer in clinical practice. Our previous studies have confirmed that FZKA shows a strong anti-cancer activity, significantly increases the clinical efficacy of gefitinib and reverses gefitinib resistance in non-small cell lung cancer (NSCLC). However, the molecular mechanism still needs to be further elucidated.

The aim of this study was to investigate the role and mechanism by which FZKA inhibited the cell growth, proliferation and invasion of lung adenocarcinoma(LUAD) and reversed the acquired resistance of gefitinib for the therapy in LUAD.

Cell viability assay and EDU assay were used for detecting of cell viability and cell proliferation. Transwell assay was performed to measure cell invasion. Western Blot and qRT-PCR were used for protein and gene expression test. The gene promoter activity was determined by dul-luciferase reporter assay. The in situ expression of protein was measured by cell immunofluorescence. Stabilized cell lines were established for stable overexpression of EZH2. Transient transfection assay was used for gene silence and overexpression. Xenograft tumors and bioluminescent imaging were used for in vivo experiments.

FZKA significantly inhibited the cell viability, proliferation and cell invasion of LUAD, the combination of FZKA and gefitinib had a great synergy on the above processes. Moreover, FZKA significantly decreased EZH2 mRNA and protein expression, FZKA reversed the resistance of gefitinib by down-regulation of EZH2 protein. ERK1/2 kinase mediated the down-regulation of EZH2 reduced by FZKA. In addition, FZKA decreased the expression of Snail and EGFR by decreasing EZH2. Overexpression of Snail and EGFR significantly reversed the effect of FZKA-inhibited cell invasion and cell proliferation. More important, the combination of FZKA and gefitinib enhanced the inhibitory effect on EZH2, Snail and EGFR proteins. Furthermore, the growth inhibition and reversal of gefitinib resistance induced by FZKA were further validated in vivo. Finally, the expression and clinical correlation of EZH2,EGFR and Snail in cancer patients were further validated using bioinformatics analysis.

FZKA significantly suppressed tumor progression and reversed gefitinib resistance by regulating the p-ERK1/2-EZH2-Snail/EGFR signaling pathway in LUAD.

Noncoding ribonucleic acids (ncRNAs) have surfaced as essential orchestrators within the intricate system of neoplastic biology. Specifically, the epidermal growth factor receptor (EGFR) signalling cascade shows a central role in the etiological underpinnings of pulmonary carcinoma. Pulmonary malignancy persists as a preeminent contributor to worldwide mortality attributable to malignant neoplasms, with non-small cell lung carcinoma (NSCLC) emerging as the most predominant histopathological subcategory. EGFR is a key driver of NSCLC, and its dysregulation is frequently associated with tumorigenesis, metastasis, and resistance to therapy. Over the past decade, researchers have unveiled a complex network of ncRNAs, encompassing microRNAs, long noncoding RNAs, and circular RNAs, which intricately regulate EGFR signalling. MicroRNAs, as versatile post-transcriptional regulators, have been shown to target various components of the EGFR pathway, influencing cancer cell proliferation, migration, and apoptosis. Additionally, ncRNAs have emerged as critical modulators of EGFR signalling, with their potential to act as scaffolds, decoys, or guides for EGFR-related proteins. Circular RNAs, a relatively recent addition to the ncRNA family, have also been implicated in EGFR signalling regulation. The clinical implications of ncRNAs in EGFR-driven lung cancer are substantial. These molecules exhibit diagnostic potential as robust biomarkers for early cancer detection and personalized treatment. Furthermore, their predictive value extends to predicting disease progression and therapeutic outcomes. Targeting ncRNAs in the EGFR pathway represents a novel therapeutic approach with promising results in preclinical and early clinical studies. This review explores the increasing evidence supporting the significant role of ncRNAs in modulating EGFR signalling in lung cancer, shedding light on their potential diagnostic, prognostic, and therapeutic implications.

Lung cancer is currently the second most common type of cancer with the second incidence rate and the first mortality rate worldwide. Non‑small cell lung cancer (NSCLC) accounts for ~85% of the total number of cases of lung cancers. Concerning the treatment of NSCLC, targeted therapy has become a research hotspot in recent years because of its favorable efficacy, high selectivity and minimal adverse reactions. Among the drugs used in targeted therapy, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the most common and are categorized into four generations. The use of first and second‑generation drugs leads to drug resistance within 8‑14 months. This resistance is primarily caused by the T790M mutation, which is the most observed mechanism. A third‑generation drug has been developed to address this issue and a fourth‑generation drug is expected to overcome multiple resistance mechanisms, including third‑generation drug resistance. However, the fourth‑generation drug has not been launched yet. At present, multiple third‑generation targeted drugs have been launched globally, with three being launched in China and several being at research and clinical trial stages. The present article provides a review of the development process, mechanism of action and clinical trials of the third‑generation EGFR‑TKIs, aiming to provide some reference and suggestions for the clinical treatment of NSCLC and scientific research on third‑generation targeted drugs.

Gefitinib, as the first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore, exploring the resistance mechanism of gefitinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC with gefitinib. Selumetinib also enhanced gefitinib-induced apoptosis and migration inhibition ability in gefitinib-resistant lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verified through the STRING database and western blotting assays. Sustained activation of STAT3 was significantly downregulated when co-treatment with selumetinib in gefitinib-resistant cells. However, the downregulation of p-STAT3, resulting from the combination of selumetinib and gefitinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced gefitinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with gefitinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and gefitinib effectively promoted the sensitivity of lung cancer xenografts to gefitinib in vivo, and the tumor inhibition rate reached 81.49%, while the tumor inhibition rate of the gefitinib monotherapy group was only 31.95%. Overall, MIG6/STAT3 negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be beneficial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.

CD147 is an important glycoprotein that participates in the progression of diverse cancers. This study aims to explore the specific function of CD147 in lung adenocarcinoma (LUAD) and to reveal related downstream molecular mechanisms.

Followed by silencing of CD147, the viability, migration, invasion, and apoptosis of LUAD cells were measured by CCK8, wound healing, transwell assay, and flow cytometer, respectively. The expression of CD147 and two markers of lipid metabolism (FASN and ACOX1) were detected by qRT-PCR. A xenograft tumor model was constructed to investigate the function of CD147 in vivo. Then transcriptome sequencing was performed to explore the potential mechanisms. After measuring the expression of Rap1 and p-p38 MAPK/p38 MAPK by western blot, the changes of CD147 and lipid metabolism markers (FASN, ACOX1) was detected by Immunohistochemistry. Moreover, a Rap1 activator and a Rap1 inhibitor were applied for feedback functional experiments.

CD147 was up-regulated in LUAD cells, and its silencing inhibited cell proliferation, migration, invasion, lipid metabolism dysregulation and promoted apoptosis, while overexpression of CD147 showed the opposite results. Silencing of CD147 also inhibited the growth of tumor xenografts in mice. Transcriptome sequencing revealed 834 up-regulated differentially expressed genes (DEGs) and 602 down-regulated DEGs. After functional enrichment, the Rap1 signaling pathway was selected as a potential target, which was then verified to be blocked by CD147 silencing. In addition, the treatment of Rap1 activator weakened the inhibiting effects of si-CD147 on the proliferation, migration, invasion, and lipid metabolism in LUAD cells, while the intervention of RAP1 inhibitor showed the opposite results.

Silencing of CD147 inhibited the proliferation, migration, invasion, lipid metabolism dysregulation and promoted apoptosis of LUAD cells through blocking the Rap1 signaling pathway.

Lung cancer is the most common type of malignant tumor that affects people in China and even across the globe, as it exhibits the highest rates of morbidity and mortality. Lung adenocarcinoma (LUAD) is a type of lung cancer with a very high incidence. The purpose of this study was to identify potential biomarkers that could be used to forecast the prognosis and improve the existing therapy options for treating LUAD. Clinical and RNA sequencing data of LUAD patients were retrieved from the TCGA database, while the mitochondria-associated gene sets were acquired from the MITOMAP database. Thereafter, Pearson correlation analysis was carried out to screen mitochondria-associated lncRNAs. Furthermore, univariate Cox and Lasso regression analyses were used for the initial screening of the target lncRNAs for prognostic lncRNAs before they could be incorporated into a multivariate Cox Hazard ratio model. Then, the clinical data, concordance index, Kaplan-Meier (K-M) curves, and the clinically-relevant subjects that were approved by the Characteristic Curves (ROC) were employed for assessing the model's predictive value. Additionally, the differences in immune-related functions and biological pathway enrichment between high- and low-risk LUAD groups were examined. Nomograms were developed to anticipate the OS rates of the patients within 1-, 3-, and 5 years, and the differences in drug sensitivity and immunological checkpoints were compared. In this study, 2175 mitochondria-associated lncRNAs were screened. Univariate, multivariate, and Lasso Cox regression analyses were carried out to select 13 lncRNAs with an independent prognostic significance, and a prognostic model was developed. The OS analysis of the established prognostic prediction model revealed significant variations between the high- and low-risk patients. The AUC-ROC values after 1, 3, and 5 years were seen to be 0.746, 0.692, and 0.726, respectively. The results suggested that the prognostic model riskscore could be used as an independent prognostic factor that differed from the other clinical characteristics. After analyzing the findings of the study, it was noted that both the risk groups showed significant differences in their immune functioning, immunological checkpoint genes, and drug sensitivity. The prognosis of patients with LUAD could be accurately and independently predicted using a risk prediction model that included 13 mitochondria-associated lncRNAs.

Lung cancer is one of the leading causes of cancer death. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Dihydrotanshinone (DHT) is a compound extract from Salvia miltiorrhiza, which has favorable anti-inflammatory and anti-cancer activities. However, the role of DHT in NSCLC has not been fully studied. The anti-cancer drugs used for treating lung cancer often lead to apoptosis; however, the drug resistance of apoptosis restricts the effect of these drugs. Oncosis is a passive form of cell death that is different from apoptosis. It is characterized by cell swelling, and Porimin is a specific marker for oncosis. In this study, the role of DHT in mediating oncosis in A549 cells was investigated. In vitro, the MTS assay was used to detect cell activity after DHT treatment. Microscopy and electron microscopy were used to observe cell morphology changes. Western blotting was used to detect protein expression. Flow cytometry was used to detect intracellular reactive oxygen species (ROS) level, calcium ion (Ca2+) level, and cell mortality. The intracellular Lactic dehydrogenase (LDH) level was detected by an LDH detection kit after DHT treatment. The ATP level was detected using an ATP detection kit. In vivo, Lewis lung cancer (LLC) xenograft mice were used to evaluate the anti-tumor effect of DHT. Hematoxylin and eosin (HE) staining was used to detect the pathology of lung cancer tumors. The detection of Porimin in the tumor tissues of the mice after DHT administration was assessed by immunohistochemistry (IHC). The results of this study showed that DHT treatment changed the cell morphology; destroyed the mitochondrial structure; increased the expression of Porimin; increased the levels of LDH, ROS, and Ca2+; decreased the mitochondrial membrane potential and ATP level; and played an anti-tumor role in vitro by mediating oncosis in A549 cells. The in vivo studies showed that DHT could effectively inhibit tumor growth. The results of protein detection and IHC detection in the tumor tissues showed that the expression of Porimin was increased and that oncosis occurred in the tumor tissues of mice. DHT triggered Porimin-dependent oncosis by ROS-mediated mitochondrial dysfunction in NSCLC. The in vivo studies showed that DHT could inhibit tumor growth in LLC xenograft mice by triggering oncosis. This study indicates the potential for DHT to treat NSCLC.

Immune checkpoints negatively regulate immune response, thereby playing an important role in maintaining immune homeostasis. Substantial studies have confirmed that blockade or deficiency of immune checkpoint pathways contributes to the deterioration of autoimmune diseases. In this context, focusing on immune checkpoints might provide alternative strategies for the treatment of autoimmunity. Lymphocyte activation gene 3 (LAG3), as a member of immune checkpoint, is critical in regulating immune responses as manifested in multiple preclinical studies and clinical trials. Recent success of dual-blockade of LAG3 and programmed death-1 in melanoma also supports the notion that LAG3 is a crucial regulator in immune tolerance.

We wrote this review article by searching the PubMed, Web of Science and Google Scholar databases.

In this review, we summarize the molecular structure and the action mechanisms of LAG3. Additionally, we highlight its roles in diverse autoimmune diseases and discuss how the manipulation of the LAG3 pathway can serve as a promising therapeutic strategy as well as its specific mechanism with the aim of filling the gaps from bench to bedside.

Based on the current difficulties in early diagnosis of HBV-related hepatocellular carcinoma (HBV-HCC), we assessed the values of preoperative serum fibrinogen-like protein 1 (FGL1) by itself and in combination with alpha-fetoprotein (AFP) for the diagnosis of HBV-HCC.

We used ELISA and chemiluminescence assays to detect the serum levels of FGL1 and AFP, respectively.

Serum FGL1 level in the HBV-HCC group was significantly higher than in the chronic HBV (CHBV) group, the liver cirrhosis (LC) group, and the healthy control (HC) group. Serum FGL1 had an outstanding performance in distinguishing AFP-negative HBV-HCC from different control conditions. In the patients with AFP-negative HBV-HCC, the sensitivity of serum FGL1 was high. Moreover, serum FGL1 had a stronger performance than AFP in distinguishing early-stage HBV-HCC.

Serum FGL1 is significantly elevated among patients with HBV-HCC, including those with negative AFP and with disease at an early stage. Hence, serum FGL1 may serve as a potential diagnostic marker in the early diagnosis of HBV-HCC.

The expression of B-cell receptor associated protein 31 (BAP31) is increased in many tumor types, and it is reported to participate in proliferation, migration, and apoptosis. However, the relationship between BAP31 and chemoresistance is uncertain. This study investigated the role of BAP31 in regulating the doxorubicin (Dox) resistance of hepatocellular carcinoma (HCC). The expression of proteins was assessed by Western blotting. The correlation between BAP31 expression and Dox resistance was examined by MTT and colony formation assays. Apoptosis was analyzed by flow cytometry and TdT-mediated dUTP nick end labeling assays. Western blot and immunofluorescence analyses were performed in the knockdown cell lines to explore the possible mechanisms. In this study, BAP31 was strongly expressed, and knockdown of BAP31 increased Dox chemosensitivity in cancer cells. Furthermore, the expression of BAP31 was higher in the Dox-resistant HCC cells than that in their parental cells; knockdown of BAP31 reduced the half maximal inhibitory concentration value and overcame Dox resistance in Dox-resistant HCC cells. In HCC cells, knockdown of BAP31 increased Dox-induced apoptosis and enhanced Dox chemosensitivity in vitro and in vivo. The potential mechanism by which BAP31 increased Dox-induced apoptosis is that BAP31 inhibited survivin expression by promoting FoxO1 nucleus-cytoplasm translocation. Knockdown of BAP31 and survivin had a synergistic effect on Dox chemosensitivity by enhancing the apoptosis of HCC cells. These findings reveal that BAP31 knockdown enhances Dox chemosensitivity through the downregulation of survivin, suggesting that BAP31 is a potential therapeutic target for improving the treatment response of HCC with resistance to Dox.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a first-line targeted drug for the treatment of advanced non-small cell lung cancer (NSCLC) in clinical practice, but EGFR-TKI-acquired resistance limits its therapeutic effect. To address this challenge, a novel multifunctional gold-based targeted nanoparticle-based drug delivery system is fabricated. The gold-based nanoparticle is loaded with the EGFR-TKI (gefitinib) and IR780, and the surface-modified gold nanoshell layer has a photothermal effect for thermally triggered drug release. Finally, the unique binding of cyclic arginine-glycine-aspartic acid (cRGD) to the α_vβ₃ receptor ensured that the nanoparticle (cRGD-GIPG) targeted transport into drug-resistant NSCLC cells was functional. Due to the sonodynamic properties of IR780, ultrasound (US) irradiation promoted reactive oxygen species (ROS) generation, while low-temperature photothermal therapy (PTT) not only promoted the release of drug, but also further enhanced the cytotoxic effects of ROS. In turn, it blocked the activation of TGF-β/PDLIM5/SMAD resistance pathway and induced apoptosis of drug-resistant cells through mitochondrial apoptosis, enabling the treatment of EGFR-TKI-resistant NSCLC. The low-temperature PTT combined with sonodynamic therapy (SDT) by cRGD-GIPG thus shows potent anticancer activity against EGFR-TKI-resistant NSCLC cells in vitro and in vivo. The present work provides a valuable strategy for highly targeted and EGFR-TKI-resistant reversal therapy in NSCLC.