Targeting KIF11 degradation: Oxypeucedanin inhibits lung adenocarcinoma progression by disrupting the MCM2-CDK1 signaling pathway.

CRABP2 Promotes Lung Adenocarcinoma Through Retinoic Acid Pathway-Mediated NF-κB Activation.

BACKGROUND Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and remains a major cause of cancer-related mortality. Despite advances in targeted therapies, tumor heterogeneity and acquired resistance frequently undermine clinical outcomes. This study aimed to identify novel oncogenic drivers and underlying mechanisms in LUAD. METHODS We examined cellular retinoic acid-binding protein 2 (CRABP2) expression in human LUAD specimens and evaluated its functional role through in vitro assays (cell proliferation, migration, invasion, and apoptosis) and in vivo xenograft tumor growth. Mechanistic exploration involved RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and immunoblotting for the nuclear factor kappa B (NF-κB) signaling components, along with rescue experiments to dissect the pathway dependency. RESULTS CRABP2 was identified as a candidate oncogene in LUAD. Functional assays confirmed that CRABP2 promoted proliferation, migration, and invasion, suppressed apoptosis, and accelerated xenograft tumor growth. Mechanistically, CRABP2 potentiated retinoic acid (RA) signaling and activated the NF-κB pathway, as evidenced by enhanced inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) phosphorylation, subsequent NF-κB inhibitor alpha (IκBα) phosphorylation, and nuclear translocation of total and phosphorylated p65. Rescue experiments revealed that CRABP2‑induced NF-κB activation is RA-dependent and that this activation mediates the oncogenic effects of CRABP2. CONCLUSIONS Our findings establish a CRABP2/RA/NF‑κB axis that drives LUAD progression, highlighting this pathway as a potential therapeutic target for intervention in LUAD.

The CRABP2-MDK Signaling Axis Promotes Lung Adenocarcinoma (LUAD) Progression and Highlights Prognostic Biomarkers.

Lung cancer is the leading cause of cancer-related mortality worldwide, with LUAD being characterized by high incidence and mortality rates. Despite the use of various treatments, including surgery, chemotherapy, immunotherapy, and molecular targeted therapy, the prognosis in LUAD patients remains unfavorable. As a result, the diagnosis and management of LUAD still present major challenges. There is an urgent need to identify novel therapeutic targets. In this study, we analyzed to explore single-cell transcriptomic data (GSE253013 dataset) to investigate epithelial cells heterogeneity in LUAD. Tumor-specific epithelial subpopulations were identified, and the signature genes were evaluated for prognostic, diagnostic potential across several GEO datasets. Functional assays were conducted to validate the role of CRABP2 in lung cancer cells. Xenograft mouse models, rescue experiments and mechanistic analyzes involving ATRA-RAR signaling were further performed to elucidate the molecular mechanism. CRABP2 expression was positively correlated with MDK in LUAD. Functional assays demonstrated that CRABP2 promoted cell proliferation, migration, invasion, and vasculogenic mimicry through activation of the MDK/VEGF/MMP2/9/AKT signaling axis. In vivo xenograft experiments further confirmed that CRABP2 knockdown suppressed tumor growth and angiogenesis. Rescue experiments identified MDK as a critical downstream effector of CRABP2. Mechanistically, CRABP2 enhanced MDK transcription via activation of the ATRA-RAR signaling pathway and increased RARA occupancy at the MDK promoter. Clinically, elevated CRABP2 expression was associated with poor prognosis and showed strong diagnostic performance in LUAD. Collectively, our findings identify CRABP2-ATRA-RAR-MDK signaling axis that drives LUAD progression and angiogenesis. CRABP2 promotes MDK transcription through activation of RAR signaling, thereby enhancing malignant phenotypes and vasculogenic mimicry. These results establish CRABP2 as a promising diagnostic and prognostic biomarker and suggest that targeting the CRABP2-MDK axis may represent a potential therapeutic strategy for LUAD.

MicroRNA320e Augments the Synthetic Lethality of Olaparib by Regulating the PI3K-AKT-mTOR Pathway

Objectives: Given the increasing drug resistance in ovarian cancer (OC), the use of poly ADP-ribose polymerase inhibitors (PARPi) for treating homologous recombination repair defects (HRD) has encountered new challenges. MicroRNA320e (miR-320e) exerts a negative regulatory role in the progression of multiple cancers. This study aimed to investigate the association between miR-320e and drug resistance in ovarian cancer. Methods: The Cell Counting Kit-8 (CCK-8) assay, migration and invasion assays, and colony formation assay were employed to evaluate the proliferation, migration, and invasion abilities of cells. Western blot (WB) analysis was used to verify the expression levels of proteins related to the relevant signaling pathways in cells. The xenograft subcutaneous tumor model was established to investigate the effect of miR-320e on in vivo tumor growth. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to detect the expression levels of related proteins and miR-320e in tumor tissues from patients and animals, respectively. Results: miR-320e was overexpressed in both A2780 and SKOV3 cells. The results showed that transfection with miR-320e significantly reduced cell proliferation, invasion, and migration, while enhancing autophagy and apoptosis. Additionally, the PI3K-AKT-mTOR signaling pathway was significantly inhibited in the treatment groups. In nude mouse models, overexpression of miR-320e also significantly suppressed tumor growth. These findings indicate that overexpression of miR-320e enhances the sensitivity of OC cells to olaparib therapy. Conclusion: In conclusion, miR-320e overexpression significantly inhibits the malignancy of ovarian cancer and increases the sensitivity of ovarian cancer cells to olaparib.

CTPS1 promotes lung adenocarcinoma progression as a targetable vulnerability.

Atranorin suppresses the LUCAT1/STAT3 axis to induce ferroptotic cell death in ovarian cancer

The ABHD10-ACSL4 axis promotes pancreatic ductal adenocarcinoma growth via suppressing ferroptosis

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis and limited treatment options. Ferroptosis has emerged as a potential therapeutic vulnerability in PDAC, but the upstream mechanisms regulating this process remain unclear. This study aimed to identify compounds with therapeutic potential against PDAC, determine their molecular targets, and elucidate how alpha/beta hydrolase domain-containing protein 10 (ABHD10) regulates tumor growth. A high-throughput compound screen against PDAC cell proliferation was performed, followed by limited proteolysis–mass spectrometry to identify the molecular target of halofuginone (HF). Target engagement was validated by surface plasmon resonance, cellular thermal shift assay, and drug affinity responsive target stability assay. Gain- and loss-of-function studies were conducted in PDAC cell lines and xenograft mouse models. Protein interaction, palmitoylation, and ferroptosis-related changes were evaluated using co-immunoprecipitation, acyl-biotinyl exchange, Click-iT labeling, transmission electron microscopy, and biochemical assays. Statistical analyses included Student’s t tests and one-way or two-way analysis of variance, as appropriate. HF significantly suppressed PDAC growth in vitro and in vivo. ABHD10 was identified as a direct binding target of HF and was upregulated in pancreatic cancer tissues and cell lines. Functional studies showed that ABHD10 promoted cell proliferation, survival, and tumor progression. Mechanistically, ABHD10 interacted with acyl-CoA synthetase long-chain family member 4 (ACSL4) and depalmitoylated it at cysteine 157, thereby suppressing ferroptosis. HF treatment or ABHD10 depletion increased ACSL4 palmitoylation, enhanced lipid peroxidation, disrupted redox homeostasis, and induced ferroptotic changes. Depletion of ACSL4 partially reversed these effects. The ABHD10–ACSL4 axis promotes PDAC growth by suppressing ferroptosis. Targeting this pathway may represent a promising therapeutic strategy for PDAC.