Demethylzeylasteral exerts potent efficacy against non-small-cell lung cancer via the P53 signaling pathway.

Lung cancer has one of the highest mortality rates worldwide, with non-small-cell lung cancer (NSCLC) constituting approximately 85% of all cases. Demethylzeylasteral (DEM), extracted from Tripterygium wilfordii Hook F, exhibits notable anti-tumor properties. In this study, we revealed that DEM could effectively induce NSCLC cell apoptosis. Specifically, DEM can dose-dependently suppress the viability and migration of human NSCLC cells. RNA-seq analysis revealed that DEM regulates the P53-signaling pathway, which was further validated by assessing crucial proteins involved in this pathway. Biacore analysis indicated that DEM has high affinity with the P53 protein. The CDX model demonstrated DEM's anti-tumor actions. This work provided evidence that DEM-P53 interaction stabilizes P53 protein and triggers downstream anti-tumor activities. These findings indicate that DEM treatment holds promise as a potential therapeutic approach for NSCLC, which warrants further clinical assessment in patients with NSCLC.

Unveiling HOXB7 as a novel diagnostic and prognostic biomarker through pan-cancer computer screening.

We attempted to investigate the role of HOXB7 in tumor progression and evolution by means of an extensive computer screening analysis of various cancer types. We performed univariate Cox regression and Kaplan-Meier survival analyses to assess the impact of HOXB7 on overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in different types of cancer. Furthermore, we examined the relationship between HOXB7 and several clinical features: tumor microenvironment, immune regulatory genes, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). We performed gene set enrichment analysis to gain deeper insights into the potential molecular mechanisms of HOXB7, and validated our findings through functional assays in cells, including methyl thiazolyl tetrazolium cytotoxicity and Transwell invasion assays. HOXB7 expression was associated with different clinical characteristics in numerous malignancies. Higher HOXB7 expression was associated with worse OS, DSS, and PFI in some cancer types. In particular, HOXB7 expression was favorably associated with immune cell infiltration, immune regulatory genes, immunological checkpoints, TMB, and MSI in malignancies. Furthermore, we identified a strong link between copper death-associated gene expression and HOXB7 expression. According to the findings of this study, HOXB7 might serve as an appealing focus for tumor diagnosis and immunotherapy and a prospective indicator of prognosis.

Repurposing diacerein to suppress colorectal cancer growth by inhibiting the DCLK1/STAT3 signaling pathway.

Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1ß inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein's specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.

Solamargine improves the therapeutic efficacy of anti-PD-L1 in lung adenocarcinoma by inhibiting STAT1 activation.

OBJECTIVE: The effect of solamargine on lung adenocarcinoma and its effect on STAT1 signaling pathway mediated immune escape were studied through network pharmacology and in vitro and in vivo experiments. METHODS: The solamargine targets were screened using the TCMSP and the LUAD targets were screened using the GeneCard, OMIM, PharmGkb, TTD and DrugBank databases. PPI network analysis and target prediction were performed using GO and KEGG. Colony formation assay, EDU staining, wound healing, transwell assay, Hoechst and flow cytometry were used to detect the effects of solamargine on the proliferation, migration and apoptosis of LUAD. Western blotting (WB) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect P-STAT1 and PD-L1 expression. And immunofluorescence was used to detect P-STAT1 expression. In vivo experiments, C57BL/6 mice were divided into control group, low concentration group, high concentration group, positive control group and combination group. Every other day, following seven consecutive doses, the size of the tumor was assessed. Finally, the expressions of P-STAT1, STAT1, PD-L1 and apoptosis index proteins were detected by WB. RESULTS: The anti-LUAD effect of solamargine was found by wound healing, colony formation assay, transwell assay, hoechst and EdU staining. The results of network pharmacological analysis showed that solamargine could suppress STAT1 expression level. Further enrichment assay of STAT1 showed that STAT1 was associated with immune-related pathways. In addition, molecular signal analysis by WB and RT-qPCR indicated that solamargine could reduce the expression levels of P-STAT1 and PD-L1 in a concentration-dependent manner. According to the results of in vivo assays, combination of solamargine and immune checkpoint inhibitors (ICIs) durvalumab could significantly inhibit the growth of Lewis transplanted tumors in C57BL/6 mice, and no toxic side effect was recoded. CONCLUSION: These results indicated that solamargine could inhibit the proliferation and promote the apoptosis of LUAD. It also could reduce the expression level of P-STAT1 protein and inhibit the expression level of PD-L1. At the same time, the combination with the ICIs can better block the expression of PD-L1 in cells, thereby inhibiting the immune escape pathway of tumor cells and achieving anti-tumor effects. This study proposed a novel combined therapeutic approach, involving the inhibition of STAT1 by solamargine in conjunction with ICIs.

Correlation between RNA N6-methyladenosine and ferroptosis in cancer: current status and prospects.

N6-methyladenosine (m6A) is the most abundant chemical modification in eukaryotic cells. It is a post-transcriptional modification of mRNA, a dynamic reversible process catalyzed by methyltransferase, demethylase, and binding proteins. Ferroptosis, a unique iron-dependent cell death, is regulated by various cell metabolic events, including many disease-related signaling pathways. And different ferroptosis inducers or inhibitors have been identified that can induce or inhibit the onset of ferroptosis through various targets and mechanisms. They have potential clinical value in the treatment of diverse diseases. Until now, it has been shown that in several cancer diseases m6A can be involved in the regulation of ferroptosis, which can impact subsequent treatment. This paper focuses on the concept, function, and biological role of m6A methylation modification and the interaction between m6A and ferroptosis, to provide new therapeutic strategies for treating malignant diseases and protecting the organism by targeting m6A to regulate ferroptosis.

CDK4/6 inhibitors in lung cancer: current practice and future directions.

Lung cancer is the leading cause of cancer-related deaths worldwide, and ∼85% of lung cancers are classified as nonsmall cell lung cancer (NSCLC). These malignancies can proliferate indefinitely, in part due to dysregulation of the cell cycle and the resulting abnormal cell growth. The specific activation of cyclin-dependent kinases 4 and 6 (CDK4/6) is closely linked to tumour proliferation. Approximately 80% of human tumours exhibit abnormalities in the cyclin D-CDK4/6-INK4-RB pathway. Specifically, CDK4/6 inhibitors either as monotherapy or combination therapy have been investigated in pre-clinical and clinical studies for the treatment of NSCLC, and promising results have been achieved. This review article focuses on research regarding the use of CDK4/6 inhibitors in NSCLC, including the characteristics and mechanisms of action of approved drugs and progress of pre-clinical and clinical research.

Cinobufagin exerts an antitumor effect in non-small-cell lung cancer by blocking STAT3 signaling.

Background: Non-small-cell lung cancer (NSCLC) is the most common histological subtype of lung cancer with significant morbidity and mortality rates worldwide. Cinobufagin, the primary component of Chansu and the major active ingredient of cinobufacini, has attracted widespread attention for its excellent anticancer effects, but its activity remains poorly characterized in NSCLC. Methods: The functions of cinobufagin treatment in anti-tumor was evaluated using various in vitro and in vivo assays. The change of STAT3 signaling by cinobufagin was analyzed using molecular docking, immunofluorescence technic and western blotting. Results: In vitro, we confirmed the inhibitory effect of cinobufagin on cell viability, proliferation, migration, epithelial-mesenchymal transition (EMT), as well as an apoptosis-inducing effect. The antitumor effects of cinobufagin were confirmed in vivo by measuring tumor growth in a mouse xenograft model. Cinobufagin was found to significantly inhibit the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at tyrosine 705 (Y705) in a time- and concentration-dependent manner. Moreover, cinobufagin reversed IL-6-induced nuclear translocation of STAT3. Conclusions: Our study has demonstrated that cinobufagin exerts an antitumor effect in non-small-cell lung cancer by blocking STAT3 signaling, and cinobufagin is a promising candidate agent for NSCLC therapy.

Acetyl-cinobufagin suppresses triple-negative breast cancer progression by inhibiting the STAT3 pathway.

BACKGROUND: The incidence of breast cancer (BC) worldwide has increased substantially in recent years. Epithelial-mesenchymal transition (EMT) refers to a crucial event impacting tumor heterogeneity. Although cinobufagin acts as an effective anticancer agent, the clinical use of cinobufagin is limited due to its strong toxicity. Acetyl-cinobufagin, a pre-drug of cinobufagin, was developed and prepared with greater efficacy and lower toxicity. METHODS: A heterograft mouse model using triple negative breast cancer (TNBC) cell lines, was used to evaluate the potency of acetyl-cinobufagin. Signal transducer and stimulator of transcription 3 (STAT3)/EMT involvement was investigated by gene knockout experiments using siRNA and Western blot analysis. RESULTS: Acetyl-cinobufagin inhibited proliferation, migration, and cell cycle S/G2 transition and promoted apoptosis in TNBC cells in vitro. In general, IL6 triggered the phosphorylation of the transcription factor STAT3 thereby activating the STAT3 pathway and inducing EMT. Mechanistically, acetyl-cinobufagin suppressed the phosphorylation of the transcription factor STAT3 and blocked the interleukin (IL6)-triggered translocation of STAT3 to the cell nucleus. In addition, acetyl-cinobufagin suppressed EMT in TNBC by inhibiting the STAT3 pathway. Experiments in an animal model of breast cancer clearly showed that acetyl-cinobufagin was able to reduce tumor growth. CONCLUSIONS: The findings of this study support the potential clinical use of acetyl-cinobufagin as a STAT3 inhibitor in TNBC adjuvant therapy.

The emerging role of the piRNA/PIWI complex in respiratory tract diseases.

PIWI-interacting RNA (piRNA) is a class of recently discovered small non-coding RNA molecules with a length of 18-33 nt that interacts with the PIWI protein to form the piRNA/PIWI complex. The PIWI family is a subfamily of Argonaute (AGO) proteins that also contain the AGO family which bind to microRNA (miRNA). Recently studies indicate that piRNAs are not specific to in the mammalian germline, they are also expressed in a tissue-specific manner in a variety of human tissues and participated in various of diseases, such as cardiovascular, neurological, and urinary tract diseases, and are especially prevalent in malignant tumors in these systems. However, the functions and abnormal expression of piRNAs in respiratory tract diseases and their underlying mechanisms remain incompletely understood. In this review, we discuss current studies summarizing the biogenetic processes, functions, and emerging roles of piRNAs in respiratory tract diseases, providing a reference value for future piRNA research.

Pharmacological targeting of MTHFD2 suppresses NSCLC via the regulation of ILK signaling pathway.

Lung cancer is the most common cause of cancer related deaths worldwide with the highest mortality rate. Non-small cell lung cancer (NSCLC) accounts for about 85 % of lung cancers. Mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme and is the most differentially expressed metabolic enzyme in various tumors including lung cancer. However, little is known about how MTHFD2 functions in NSCLC. Integrin-linked kinase (ILK) signaling plays key a role in tumor progression including metastasis, proliferation and migration. Here, we show that MTHFD2 inhibition results in suppression of cell growth, migration, invasion and epithelial-mesenchymal transition (EMT) in NSCLC. Microarray analysis suggests that MTHFD2 is positively associated with ILK signaling based on western blotting results. In addition, the phosphorylation of AMPKα plays an essential role in MTHFD2 regulation of ILK signaling. Further, the small-molecule compound C18 inhibits MTHFD2 with great efficiency. C18 blocks MTHFD2/ILK signaling pathway and restrains cell growth, migration, invasion, and EMT of NSCLC and induces apoptosis. In brief, our study found that the positive impact of MTHFD2 is mediated via ILK signaling pathway in NSCLC. Thus, blocking MTHFD2 represents a promising therapeutic strategy against NSCLC clinically.

Celastrol elicits antitumor effects by inhibiting the STAT3 pathway through ROS accumulation in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common lung cancer with high mortality across the world, but it is challenging to develop an effective therapy for NSCLC. Celastrol is a natural bioactive compound, which has been found to possess potential antitumor activity. However, the underlying molecular mechanisms of celastrol activity in NSCLC remain elusive. METHODS: Cellular function assays were performed to study the suppressive role of celastrol in human NSCLC cells (H460, PC-9, and H520) and human bronchial epithelial cells BEAS-2B. Cell apoptosis levels were analyzed by flow cytometry, Hoechst 33342, caspase-3 activity analysis, and western blot analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry and fluorescence microscope. Expression levels of endoplasmic reticulum (ER) stress-related proteins and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) were identified via western blot analysis. A heterograft model in nude mice was employed to evaluate the effect of celastrol in vivo. RESULTS: Celastrol suppressed the growth, proliferation, and metastasis of NSCLC cells. Celastrol significantly increased the level of intracellular ROS; thus, triggering the activation of the ER stress pathway and inhibition of the P-STAT3 pathway, and eventually leading to cell apoptosis, and the effects were reversed by the pre-treatment with N-Acetyl-L-cysteine (NAC). Celastrol also suppressed tumor growth in vivo. CONCLUSION: The outcomes revealed that celastrol plays a potent suppressive role in NSCLC in vitro and in vivo. Celastrol induces apoptosis via causing mitochondrial ROS accumulation to suppress the STAT3 pathway. Celastrol may have potential application prospects in the therapy of NSCLC.

GPR37 promotes cancer growth by binding to CDK6 and represents a new theranostic target in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is associated with poor prognosis. Identifying novel cancer targets and helpful therapeutic strategies remains a serious clinical challenge. This study detected differentially expressed genes in The Cancer Genome Atlas (TCGA) LUAD data collection. We also identified a predictive DNA biomarker, G protein-coupled receptor 37 (GPR37), which was verified as a prognostic biomarker with a critical role in tumor progression. In human LUAD specimens and microarray analyses, we determined that GPR37 was significantly upregulated and associated with a poor prognosis. GPR37 downregulation markedly inhibited the proliferation and migration of LUAD both in vitro and in vivo. Mechanistically, GPR37 could bind to CDK6, thereby facilitating tumor progression in LUAD by inducing cell cycle arrest at the G1 phase. GPR37 also facilitates tumorigenesis in xenograft tumors in vivo. High-throughput screening for GPR37-targeted drugs was performed using the Natural Products Library, which revealed the potential of Hypocrellin B to inhibit GPR37 and cell growth in LUAD. We demonstrated that Hypocrellin B suppressed LUAD cell proliferation and migration both in vitro and in vivo via GPR37 inhibition. Collectively, our findings reveal the role of GPR37 in LUAD progression and migration and the potential of GPR37 as a target for the treatment of LUAD. Thus, the specific inhibition of GPR37 by the natural product Hypocrellin B may possess the potential for the treatment of LUAD.

Acetylshikonin exerts anti-tumor effects on non-small cell lung cancer through dual inhibition of STAT3 and EGFR.

BACKGROUND: Lung cancer is one of the most common types of malignant tumor. It has one of the highest morbidity and mortality rates worldwide, and approximately 85% of cases are non-small cell lung cancer (NSCLC). Clinically, several EGFR inhibitors have been used to treat NSCLC, but resistance can develop. Studies have shown that cross talk between signal transducer and activator of transcription 3 (STAT3) and epidermal growth factor receptor (EGFR) can mediate drug resistance. Acetylshikonin has obvious antitumor effects, but the mechanism of action is still unclear. PURPOSE: To analyze the antitumor activity of acetylshikonin in lung cancer and clarify its molecular mechanism. METHODS: Methyl thiazolyl tetrazolium (MTT), colony formation and 5-ethynyl-2'-deoxyuridine (EDU) assays were performed to examine the effects of acetylshikonin in inhibiting the proliferation of NSCLC cells (PC-9, H1975 and A549). Scratch wound and transwell assays were used to evaluate the migration and invasion of NSCLC cells. Flow cytometry was employed to determine whether acetylshikonin could induce apoptosis. Proteome sequencing was used to identify the targets of acetylshikonin. Immunofluorescence staining and western blotting were utilized to verify the inhibition of STAT3 and EGFR phosphorylation. A xenotransplantation model was established to evaluate the efficacy of acetylshikonin in nude mice. RESULTS: Our data demonstrated that acetylshikonin significantly decreased the survival rate of human NSCLC cells, increased the apoptotic rate and inhibited cell migration dose-dependently. Immunofluorescence staining and western blotting analyses revealed that acetylshikonin inhibited EGFR and STAT3 pathways. Acetylshikonin also inhibited tumor growth in a xenograft model better than inhibitors of EGFR and STAT3. CONCLUSION: Acetylshikonin has anti-cancer effects on NSCLC cells by inhibiting EGFR and STAT3, indicating that acetylshikonin may be a new antitumor drug to treat NSCLC.

Roles of Embryonic Lethal Abnormal Vision-Like RNA Binding Proteins in Cancer and Beyond.

Embryonic lethal abnormal vision-like (ELAVL) proteins are RNA binding proteins that were originally discovered as indispensable regulators of the development and functioning of the nervous system. Subsequent studies have shown that ELAVL proteins not only exist in the nervous system, but also have regulatory effects in other tissues. ELAVL proteins have attracted attention as potential therapeutic targets because they stabilize multiple mRNAs by binding within the 3'-untranslated region and thus promote the development of tumors, including hepatocellular carcinoma, pancreatic cancer, ovarian cancer, breast cancer, colorectal carcinoma and lung cancer. Previous studies have focused on these important relationships with downstream mRNAs, but emerging studies suggest that ELAVL proteins also interact with non-coding RNAs. In this review, we will summarize the relationship of the ELAVL protein family with mRNA and non-coding RNA and the roles of ELAVL protein family members in a variety of physiological and pathological processes.

AT7519 against lung cancer via the IL6/STAT3 signaling pathway.

Lung cancer is a part of the commonest malignancies with the highest mortality rate in cancer-related deaths worldwide. Signal transducer and activator of transcription 3 (STAT3) and cyclin-dependent kinases (CDKs) are promising prognostic marker and therapeutic target in cancers. Our previous study has demonstrated the closely relationship between CDK9 and STAT3 in lung cancer. The inhibition of cell viability and migration in vitro by AT7519 were evaluated using methyl thiazolyl tetrazolium (MTT) assay, clonogenic assay and scratch wound model. The cell cycle analysis was evaluated using flow cytometry analysis and western blotting analysis. The apoptotic-induced efficiency was assessed by flow cytometry analysis, hoechst 33342 staining, caspase-3 activity analysis and western blotting analysis. The roles of STAT3 in AT7519 treatment for lung cancer were assessed by docking model and western blotting analysis. The patient-derived xenograft (PDX) models were used to investigate the effect of AT7519 in vivo. In this study, we found that AT7519, a CDK inhibitor, reduced the viability of lung cancer cells in vitro and strongly suppressed tumor growth in PDX model. AT7519 blocked cell cycle progression and induced apoptosis by inhibiting IL-6/STAT3 pathway. Taken together, AT519 exhibits great anti-tumor effects in lung cancer, and the mechanism was related closely to IL-6/STAT3 signaling pathway, which suggests the important roles of STAT3 in CDKs inhibitors. AT7519 might be a novel potential therapeutic agent based on this rationale.

Telocinobufagin Has Antitumor Effects in Non-Small-Cell Lung Cancer by Inhibiting STAT3 Signaling.

Non-small-cell lung carcer (NSCLC), the main histological subtype of lung cancer, is responsible for significant morbidity and mortality worldwide. Telocinobufagin, an active compound of the Chinese traditional medicine ChanSu, has antitumor effects, but its mechanism of action remains unknown. Therefore, we investigated the effect of telocinobufagin on NSCLC growth and metastasis and its possible mechanism of action, in vitro and in vivo. Cell proliferation, migration, and apoptosis were measured by methyl thiazol tetrazolium assay, colony formation, 5-ethynyl-2'-deoxyuridine incorporation, Transwell migration, wound healing, and flow cytometry analysis. A mouse xenograft model was used to evaluate tumor formation in vivo. Telocinobufagin was found to suppress proliferation and metastasis and induce apoptosis in human NSCLC cells. Moreover, telocinobufagin was able to significantly inhibit STAT3 phosphorylation at tyrosine 705 (Y705) and its downstream targets. Additionally, telocinobufagin also impaired the IL-6-induced nuclear translocation of STAT3. Consistent with the in vitro experiments, telocinobufagin reduced the A549 xenograft tumor burden and the levels of P-STAT3Y705, MCL1, BCL2, and cleaved PARP1 in vivo. These results support telocinobufagin as a promising STAT3 signaling inhibitor candidate for the treatment of NSCLC patients.

Hypocrellin A exerts antitumor effects by inhibiting the FGFR1 signaling pathway in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer, which is the deadliest form of cancer worldwide. Recent studies have shown that genes in the fibroblast growth factor (FGF) family are highly mutated in lung cancer, and fibroblast growth factor receptor 1 (FGFR1) has been found to be involved in various cancers, including lung cancer, suggesting that FGFR1 is a valid therapeutic target. Hypocrellin A (HA), a molecule with multiple biological activities, has been shown to influence cancer growth, but the specific mechanisms of its antitumor action have not been fully explored. METHODS: MTT, colony formation, wound healing, transwell cell invasion and EdU cell proliferation assays were performed upon HA treatment of three NSCLC cell lines, H460, PC-9 and H1975. Hoechst 33258 staining and caspase 3 activity assays were carried out to investigate the impact of HA on apoptosis in these cells. Molecular docking and surface plasmon resonance were conducted to assess binding of HA to FGFR1. A mouse tumor model was used to detect the NSCLC-inhibitory ability of HA in vivo. RESULTS: Through in vitro assays, HA was shown to negatively impact cell viability, migration, invasion and promote apoptosis in three human NSCLC cell line models. HA was shown to bind to FGFR1 and to inhibit its autophosphorylation and the phosphorylation of downstream signaling molecules. Inhibition of tumor growth was also demonstrated in a mouse xenograft tumor model, and no toxic effects of HA treatment were observed. CONCLUSIONS: HA inhibits the activity of the FGFR1 and STAT3 signaling pathways. HA thus represents a potential new FGFR1-targeted treatment for NSCLC.

Necroptosis-related lncRNAs: Combination of bulk and single-cell sequencing reveals immune landscape alteration and a novel prognosis stratification approach in lung adenocarcinoma.

Necroptosis, which is recently recognized as a form of programmed cell death, plays a critical role in cancer biology, including tumorigenesis and cancer immunology. It was recognized not only to defend against tumor progression by suppressing adaptive immune responses but also to promote tumorigenesis and cancer metastasis after recruiting inflammatory responses. Thus the crucial role of necrosis in tumorigenesis has attracted increasing attention. Due to the heterogeneity of the tumor immune microenvironment (TIME) in lung adenocarcinoma (LUAD), the prognosis and the response to immunotherapy vary distinctly across patients, underscoring the need for a stratification algorithm for clinical practice. Although previous studies have formulated the crucial role of lncRNAs in tumorigenicity, the relationship between necroptosis-related lncRNAs, TIME, and the prognosis of patients with LUAD was still elusive. In the current study, a robust and novel prognostic stratification model based on Necroptosis-related LncRNA Risk Scoring (NecroLRS) and clinicopathological parameters was constructed and systemically validated in both internal and external validation cohorts. The expression profile of four key lncRNAs was further validated by qRT-PCR in 4 human LUAD cell lines. And a novel immune landscape alteration was observed between NecroLRS-High and -Low patients. To further elucidate the mechanism of necroptosis in the prognosis of LUAD from a single-cell perspective, a novel stratification algorithm based on K-means clustering was introduced to extract both malignant and NecroLRS-High subsets from epithelial cells. And the necroptosis-related immune infiltration landscape and developmental trajectory were investigated respectively. Critically, NecroLRS was found to be positively correlated with neutrophil enrichment, inflammatory immune response, and malignant phenotypes of LUAD. In addition, novel ligand-receptor pairs between NecroLRS-High cells and other immunocytes were investigated and optimal therapeutic compounds were screened to provide potential targets for future studies. Taken together, our findings reveal emerging mechanisms of necroptosis-induced immune microenvironment alteration on the deteriorative prognosis and may contribute to improved prognosis and individualized precision therapy for patients with LUAD.

Targeting cyclin-dependent kinase 9 in cancer therapy.

Cyclin-dependent kinase (CDK) 9 associates mainly with cyclin T1 and forms the positive transcription elongation factor b (p-TEFb) complex responsible for transcriptional regulation. It has been shown that CDK9 modulates the expression and activity of oncogenes, such as MYC and murine double minute 4 (MDM4), and it also plays an important role in development and/or maintenance of the malignant cell phenotype. Malfunction of CDK9 is frequently observed in numerous cancers. Recent studies have highlighted the function of CDK9 through a variety of mechanisms in cancers, including the formation of new complexes and epigenetic alterations. Due to the importance of CDK9 activation in cancer cells, CDK9 inhibitors have emerged as promising candidates for cancer therapy. Natural product-derived and chemically synthesized CDK9 inhibitors are being examined in preclinical and clinical research. In this review, we summarize the current knowledge on the role of CDK9 in transcriptional regulation, epigenetic regulation, and different cellular factor interactions, focusing on new advances. We show the importance of CDK9 in mediating tumorigenesis and tumor progression. Then, we provide an overview of some CDK9 inhibitors supported by multiple oncologic preclinical and clinical investigations. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.