Lung cancer is the leading cause of cancer-related mortality globally. N6-methyladenosine (m6A) is the most abundant modification in mammalian mRNA and is involved in the biological regulation of tumors, including lung cancer. However, the role of m6A-related proteins, such as RNA-binding motif protein 15 (RBM15), in lung cancer progression remains largely unknown. Our study indicated that RBM15 is significantly overexpressed in lung adenocarcinoma, serving as an independent prognostic factor for poor outcomes and facilitating tumor cell proliferation and migration. RBM15 was markedly elevated in patients with EGFR mutations, correlating with a poorer prognosis, while it had negligible prognostic value in EGFR wild-type patients. As EGFR-tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with EGFR mutations, we subsequently determined that RBM15 drives osimertinib resistance via a novel mechanism: enhancing m6A modification of cwcv- and kazal-like domains proteoglycan 1 (SPOCK1) mRNA, promoting epithelial–mesenchymal transition-mediated osimertinib resistance through a bypass activation pathway. These findings were validated in osimertinib-resistant H1975 cells and organoids from patients with osimertinib-resistant lung adenocarcinoma. Furthermore, the RBM15–SPOCK1 axis was activated in drug-tolerant persister cells, indicating that early targeting of RBM15 during EGFR-TKI treatment could dramatically extend the patient response and benefit from TKI therapy. Our results emphasize the critical role of RBM15 in reversing EGFR-TKI resistance and propose it as a promising therapeutic target for prolonging TKI treatment benefits in patients with lung adenocarcinoma.

Over the last decade, researchers have paid more and more attention to the natural compound curcumin for its potential application in anticancer therapy. However, the application of curcumin has been limited owing to its rapid metabolism in the body. HO‐3867, a stable curcumin analog, shows potent antitumor activities against various tumor cells. Yet, information on HO‐3867’s impact on non‐small‐cell lung cancer (NSCLC) cells is lacking. Herein, we evaluated the cytotoxicity of HO‐3867 in NSCLC cells. We discovered that HO‐3867 suppressed the viability of NSCLC cells containing wild‐type p53. In NSCLC cells, HO‐3867 promotes both apoptosis and ferroptosis, the latter of which is a newly discovered mode of cell death. Mechanically, HO‐3867‐induced apoptosis relied on the inhibition of Mcl‐1 and Bcl‐2 and the upregulation of Bax. Moreover, NSCLC cells undergo ferroptosis when treated with HO‐3867 via activating the p53‐DMT1 axis and suppressing GPX4. Additionally, HO‐3867 caused an accumulation of reactive oxygen species (ROS) in NSCLC in a way that was dependent on the presence of iron. Our findings point to the possibility that HO‐3867 might be employed as a therapeutic agent for treating NSCLC.

Immune checkpoint inhibitors have revolutionized non-small cell lung cancer (NSCLC) treatment but may pose greater technical challenges for surgery. This study aims to assess the feasibility and oncological effectiveness of video-assisted thoracoscopic surgery (VATS) for resectable stage III NSCLC after neoadjuvant immunochemotherapy. Initial stage IIIA-IIIB NSCLC patients with neoadjuvant immunochemotherapy undergoing either VATS or open lobectomy at 6 medical centers during 2019-2023 were retrospectively identified. Perioperative outcomes and 2-year survival was analyzed. Propensity-score matching (PSM) was employed to balance patient baseline characteristics. Among the total 143 patients, PSM yielded 62 cases each for VATS and OPEN groups. Induction-related adverse events were comparable between the 2 groups. VATS showed a 14.5% conversion rate. Notably, VATS decreased numeric rating scales for postoperative pain, shortened chest tube duration (5[4-7] vs. 6[5-8] days, P = .021), reduced postoperative comorbidities (21.0% vs. 37.1%, P = .048), and dissected less N1 lymph nodes (5[4-6] vs. 7[5-9], P = .005) compared with thoracotomy. Even when converted, VATS achieves perioperative outcomes equivalent to thoracotomy. Additionally, over a median follow-up of 29.5 months, VATS and thoracotomy demonstrated comparable 2-year recurrence-free survival (77.20% vs. 73.73%, P = .640), overall survival (87.22% vs. 88.00%, P = .738), cumulative incidences of cancer-related death, and recurrence patterns. Subsequent subgroup comparisons and multivariate Cox analysis likewise revealed no statistical difference between VATS and thoracotomy. VATS is a viable and effective option for resectable stage III NSCLC patients following neoadjuvant immunochemotherapy, leading to decreased surgical-related pain, earlier chest tube removal, reduced postoperative complications, and similar survival outcomes compared to thoracotomy.

Backgrounds: As a regulator of cell cycle, cell division cycle‐associated 5 (CDCA5) is involved in the progression of various malignant tumors. However, the potential relationship between CDCA5 and lung cancer has not been reported.Methods: In our study, we analyzed the expression of CDCA5 in a variety of malignant tumors, performed Kaplan‐Meier survival analysis of lung adenocarcinoma (LUAD), explored the potential relationship between CDCA5 expression and clinicopathological characteristics, assessed the predictive capability of at different stages of clinicopathological characteristics, revealed the enriched functions and signaling pathways among LUAD paitents with high CDCA5 expression, and investigated the correlation between PD‐1, PD‐L1, and CDCA5 through bioinformatics analyses. Subsequently, we performed quantitative real‐time reverse transcription‐polymerase chain reaction (qRT‐PCR) and western blotting (WB) to demonstrate that CDCA5 mediates the p53‐p21 pathway and regulates the cell cycle.Result: CDCA5 is probably involved in the occurrence and development of NSCLC, and function as a reliable biomarker for predicting the survival outcomes of patients with early stage of patients with LUAD. Furthermore, CDCA5 may be a promising indicator of immunotherapy efficacy. In addition, silencing the expression of CDCA5 significantly increased the proportion of apoptotic NSCLC cells, and caused NSCLC cells to be arrested in the G1 phase.Conslusion: In conclusion, CDCA5 regulated the cell cycle of NSCLC cells by mediating the p53‐p21 signaling pathway, participating in the development and progression of NSCLC patients.

Autophagy is closely associated with the tumor immune microenvironment (TIME) and prognosis of patients with lung adenocarcinoma (LUAD). In the present study, we established a signature on the basis of long noncoding RNAs (lncRNAs) related to autophagy (ARlncRNAs) to investigate the TIME and survival of patients with LUAD. We selected ARlncRNAs associated with prognosis to construct a model and divided each sample into different groups on the basis of risk score. The ARlncRNA signature could be recognized as an independent prognostic factor for patients with LUAD, and patients in the low-risk group had a greater survival advantage. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis suggested that several immune functions and pathways were enriched in different groups. A high-risk score correlated significantly negatively with high abundance of immune cells and stromal cells around the tumor and high tumor mutational burden. Low-risk patients had a higher PD-1, CTLA-4, and HAVCR2 expression and had a better efficacy of immune checkpoint inhibitors, including PD-1/CTLA-4 inhibitor. A reliable signature on the basis of ARlncRNAs was constructed to explore the TIME and prognosis of patients with LUAD, which could provide valuable information for individualized LUAD treatment.

The tumor immune microenvironment of lung cancer is associated with prognosis and immunotherapy efficacy. Long noncoding RNAs are identified as prognostic biomarkers associated with immune functions. We constructed a signature comprising differentially expressed immune-related lncRNAs to predict the prognosis of patients with lung adenocarcinoma. We established the immune-related lncRNA signature by pairing immune-related lncRNAs regardless of expression level and lung adenocarcinoma patients were divided into high- and low-risk groups. The prognosis of patients in the two groups was significantly different; The immune-related lncRNA signature could serve as an independent lung adenocarcinoma prognostic indicator. The signature correlated negatively with B cell, CD4+ T cell, M2 macrophage, neutrophil, and monocyte immune infiltration. Patients with low risk scores had a higher abundance of immune cells and stromal cells around the tumor. Gene set enrichment analysis showed that samples from low-risk group were more active in the IgA production in intestinal immune network and the T and B cell receptor signaling pathway. High-risk groups had significant involvement of the cell cycle, DNA replication, adherens junction, actin cytoskeleton regulation, pathways in cancer, and TGF-β signaling pathways. High risk scores correlated significantly negatively with high CTLA-4 and HAVCR2 expression and higher median inhibitory concentration of common anti-tumor chemotherapeutics (e.g., cisplatin, paclitaxel, gemcitabine) and targeted therapy (e.g., erlotinib and gefitinib). We identified a reliable immune-related lncRNA lung adenocarcinoma prognosis model, and the immune-related lncRNA signature showed promising clinical prediction value.