RepID orchestrates CDH1 and CTNNB1 homeostasis to regulate metastatic potential in small cell lung cancer.

NUPR1 in breast cancer: mechanisms and potential applications

Breast cancer continues to present formidable clinical challenges, particularly in triple-negative and endocrine-resistant subtypes where adaptive stress mechanisms drive therapeutic failure. Nuclear protein 1 (NUPR1), an intrinsically disordered protein, has emerged as a non-mutational hub that has been implicated in integrating metabolic, transcriptional, and cell-survival signals associated with malignant progression. This Review examines how NUPR1 transduces mitogenic stimuli into anabolic programs, while orchestrating autophagic flux, lysosomal biogenesis, and ferroptosis evasion to maintain cellular fitness under oncogenic and therapeutic stress. We discuss its causal roles in endocrine and chemoresistance through chromatin-associated cooperation with estrogen receptor α, activation of DNA-damage repair, and cell-cycle checkpoint control, as well as its contributions to metastatic dissemination via extracellular vesicle-mediated niche remodeling and immunosuppressive macrophage polarization. Furthermore, we evaluate emerging therapeutic avenues, from small-molecule inhibitors and single-domain antibody degraders that disrupt NUPR1 nuclear trafficking, to metabolic drug repurposing strategies such as statins that intercept the insulin–NUPR1 axis. Elucidating NUPR1 biology represents a paradigm shift toward targeting dynamic, stress-adaptive dependencies in breast cancer, offering new precision-oncology opportunities.

IQGAP2 regulates phagocytic-like activity and PD-L1 expression in glioma through the JAK2/STAT3 axis

ZBTB33/RBM15 Axis Upregulates MACC1 to Promote the Malignant Progression of Colorectal Cancer.

BACKGROUND Extensive clinical evidence has identified metastasis-associated colon cancer 1 (MACC1) as a pivotal cancer-promoting gene that actively fuels the advancement of neoplasms. However, the upstream transcriptional regulators of MACC1 and the specific posttranscriptional mechanisms involving N6-methyladenosine (m6A) modification that govern its expression remain largely undefined. This study aims to elucidate the regulatory network controlling MACC1 expression and its impact on colorectal cancer (CRC) progression. METHODS MACC1 expression and its potential regulators were systematically analyzed using public databases, including GEPIA, TCGA, and TIMER2, alongside clinical tissue samples and cell lines (SW480, HCT-116, and SW620). Functional experiments were conducted to assess cell viability, proliferation, invasion, and ferroptosis. These methodological approaches encompassed chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), as well as dual-luciferase reporter systems. Furthermore, in vivo validation was performed using a nude mouse xenograft model. RESULTS MACC1 was significantly upregulated in CRC tissues and cell lines, and its high expression correlated with an unfavorable prognosis. Functional assays revealed that silencing MACC1 inhibited CRC cell proliferation and invasion while inducing ferroptosis. Mechanistically, RNA binding protein 15 (RBM15) was identified as a key m6A methyltransferase component that stabilized MACC1 mRNA in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)- dependent manner. Furthermore, zinc finger and BTB domain-containing 33 (ZBTB33) was found to transcriptionally activate RBM15 by binding to its promoter region. Knockdown of RBM15 inhibited CRC cell invasion and proliferation and induced ferroptosis; these effects were notably reversed by MACC1 overexpression. Moreover, ZBTB33 silencing inhibited the key malignant phenotypes of CRC cells and induced ferroptosis by regulating RBM15. Further, RBM15 depletion suppressed tumor growth, which was attenuated by the restoration of MACC1. DISCUSSION Our study unveils a novel ZBTB33/RBM15/MACC1 signaling axis that drives CRC progression. Clinically, these findings not only deepen the understanding of m6A-mediated posttranscriptional regulation in CRC but also identify this axis as a promising therapeutic target for overcoming ferroptosis resistance and improving patient outcomes. CONCLUSION These findings uncover a novel ZBTB33/RBM15/MACC1 regulatory axis in CRC, where ZBTB33 transcriptionally activates RBM15 to enhance MACC1 mRNA stability, ultimately suppressing ferroptosis and promoting tumor progression.

Multiomics Analysis Reveals CTHRC1+ CAFs Drive Immunosuppressive Niches and Predict Immunotherapy Resistance in Gastric Cancer

Cancer‐associated fibroblasts (CAFs) orchestrate immune‐excluded tumor microenvironment (TME), but the CAF heterogeneity remains incompletely understood in gastric cancer (GC). In this study, we integrated multicohort single‐cell RNA sequencing (scRNA‐seq), spatial transcriptomics, and bulk transcriptomic data to construct a comprehensive atlas of the GC TME. Unsupervised clustering identified eight transcriptionally distinct CAF subpopulations, among which CTHRC1+ CAFs were selectively enriched in tumors and showed the strongest association with T cell exclusion. Pseudotemporal trajectory analysis, gene regulatory network inference, and cell–cell communication analysis revealed that basic helix‐loop‐helix family member e41 (BHLHE41) serves as a key transcription factor driving CTHRC1+ CAF differentiation, whereas spatial analyses demonstrated these fibroblasts contribute to fibrotic niches at the tumor–stroma interface through macrophage migration inhibitory factor (MIF)–mediated signaling. Finally, we developed and validated a CTHRC1+ cancer‐associated fibroblast–related risk signature (CRS) that accurately predicts immunotherapy response across independent cohorts. These findings establish CTHRC1+ CAFs as a critical stromal determinant of immune exclusion in GC, suggesting that targeting the CTHRC1+ CAF‐MIF axis or applying CRS‐guided patient stratification may enhance immunotherapy efficacy.

Metalloprotease-driven remodeling of PTK7 and the cell surfaceome promotes metastatic fitness of circulating colorectal tumor cells

TRDMT1 Slows Lung Cancer Growth by Stabilizing TFRC mRNA and Triggering Ferroptosis Cell Death.

Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, remains a significant therapeutic challenge due to its high mortality rates, driven by both inherent and acquired resistance to standard therapies. Emerging evidence highlights the role of epitranscriptomic regulation, particularly RNA modifications such as 5-methylcytosine (m5C), in the pathogenesis of cancer. This study identifies TRDMT1 (DNMT2), an m5C methyltransferase, as a tumor suppressor in LUAD. It was found that TRDMT1 expression is significantly lower in LUAD tissues, and this reduction is associated with poor prognosis in patients. Functional assays indicated that TRDMT1 inhibits the proliferation, migration, and invasion of LUAD cells in vitro. Mechanistically, transcriptomic profiling and subsequent investigation revealed that TRDMT1 enhances the stability of transferrin receptor (TFRC) mRNA in an m5C-dependent manner. This post-transcriptional regulation leads to TFRC upregulation, which subsequently disrupts intracellular iron homeostasis, culminating in increased susceptibility to ferroptosis-an iron-dependent form of regulated cell death. Rescue experiments confirmed that the tumor-suppressive and pro-ferroptotic effects of TRDMT1 are mediated through TFRC. This study unveils a novel TRDMT1-TFRC regulatory axis that suppresses LUAD progression through the modulation of ferroptosis, highlighting this pathway as a promising therapeutic target for future interventions.