Lung cancer remains the leading cause of cancer-related mortality worldwide in both males and females. Despite recent advances in precision-targeted therapeutics, mortality rates remain high, largely due to delayed diagnoses when curative interventions are no longer feasible. Recent studies from our group demonstrated that the LINE-1 mRNA and associated miRNA cargo of plasma exosomes can be used as sensitive and specific diagnostic and prognostic biomarkers of non-small-cell lung cancer (NSCLC). Because exosomes from various cancer types can be detected in urine, we extended our investigation to examine these analytes in urine exosomes from NSCLC patients. LINE-1 ORF1 and ORF2 mRNA levels, along with miR-21-5p, miR-126-3p, miR-210-3p, miR-221-3p, Let-7b-5p, miR-146a-5p, miR-222-3p, miR-9-5p, and miR-1277-5p, were higher in urine exosomes from NSCLC patients compared to healthy controls. The cargo of urine-derived exosomes often mirrored that of plasma exosomes and correlated with several clinicopathologic characteristics. The strong predictive performance of urine exosomal RNAs distinguishing NSCLC patients from controls suggests these measurements may serve as a complementary and readily accessible source for noninvasive assessment of patients with NSCLC.

Testicular receptor 4 (TR4, NR2C2) is an orphan nuclear receptor involved in the regulation of metabolism, inflammation, cardiovascular disease, and cancer. Accumulating evidence indicates that TR4 exhibits functional plasticity, exerting protective or pathogenic effects depending on tissue and disease context, and sometimes displaying opposing roles within the same disease. However, the mechanisms underlying this functional duality remain poorly understood. Recent studies indicate that TR4 activity is determined not only by the receptor itself but also by dynamic coregulatory networks. Through interactions with coactivators, corepressors, epigenetic regulators, and environmental signaling pathways, TR4 integrates metabolic cues to generate context-dependent transcriptional programs. Coactivator networks centered on PGC-1α, steroid receptor coactivator (SRC) family members, and CBP/p300 support oxidative metabolism and anti-inflammatory responses, whereas RIP140-, NCoR/SMRT-, and HDAC-associated networks promote lipid accumulation, chronic inflammation, fibrosis, and tumor progression. Regulators such as JAZF1 further influence TR4 activity by reshaping coregulator recruitment and target-gene selection. In this review, we summarize the structural basis of TR4 regulation and discuss how coregulatory network remodeling governs its functions in metabolic, cardiovascular, inflammatory, and malignant diseases. We propose that TR4 functions as a context-dependent transcriptional platform whose activities are defined by its coregulatory landscape, providing a framework for precision therapies.

Tumor-associated macrophages (TAMs) are among the most important myeloid cell populations in the tumor microenvironment of digestive system tumors and are characterized by marked plasticity, heterogeneity, and context dependence. This review focuses on gastric, colorectal, liver, and pancreatic cancers as representative digestive system solid tumors in which TAM spatial organization has been increasingly characterized by single-cell and spatial omics studies. Traditional M1/M2 polarization or fixed subtype-based classification is insufficient to capture the continuous state transitions of TAMs across tumor types, disease stages, and tissue regions. Recent evidence suggests that TAM heterogeneity reflects dynamic functional states shaped within distinct spatial niches by local oxygen supply, metabolic stress, stromal architecture, vascular status, and interactions with neighboring cells. From a spatial-niche perspective, this review synthesizes current evidence on TAM distribution patterns, phenotypic changes, and functional biases across six recurrent spatial contexts: the hypoxic core, invasive front, fibrotic septa, perivascular regions, tertiary lymphoid structure (TLS)-adjacent regions, and necrotic borders. By linking these niches with cross-niche functional axes and evidence-supported molecular programs, we provide a structured niche-to-function framework for comparing TAM spatial heterogeneity and its major functional dimensions, including metabolic adaptation, tissue remodeling, and immune-inflammatory regulation. This context-sensitive framework may help guide future studies of niche-specific TAM reprogramming and rational combinations with immunotherapy and other treatment strategies.

Angiopoietin-like 3 (ANGPTL3) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are key regulators of lipid homeostasis. We have previously shown that gene silencing of ANGPTL3 significantly induces PCSK9 expression in the human hepatoma cell line Huh7. Here, we investigated the biological significance of this regulation in the cultured human hepatoma cell line Huh7.

We performed an RNA-seq analysis in Huh7 cells transfected with siRNA-ANGPTL3, siRNA-PCSK9, and double siRNA-ANGPTL3/PCSK9. Selected findings were assessed by RT-qPCR, Western blotting, and ELISA.

Among 13,945 detected transcripts, 192 genes were differentially expressed after ANGPTL3 silencing, 88 after PCSK9 silencing, and 219 after combined ANGPTL3/PCSK9 silencing, compared with scramble-siRNA controls. When ANGPTL3 gene expression was silenced, we observed a compensatory induction in PCSK9 mRNA and protein expression. Bioinformatic analysis revealed that gene silencing of ANGPTL3 or both ANGPTL3/PCSK9 suppresses serpin family A member 1 (SERPINA1), which encodes α1-antitrypsin, and lectin mannose-binding 1 (LMAN1). These data were confirmed by Western blot and RT-PCR analysis. In addition, ANGPTL3-siRNA, alone or combined with PCSK9-siRNA, significantly increased FV and FVIII mRNA expression and secretion in conditioned medium.

Our data identified SERPINA1 and LMAN1 as genes downregulated in response to ANGPTL3 silencing in Huh7 hepatoma cells, which was also associated with increased expression of FV and FVIII. Our study suggests a potential link between ANGPTL3 silencing and coagulation-related processes, extending the biological relevance of ANGPTL3 beyond lipid metabolism.

The study investigates the impact of molecular iodine (I₂) supplementation on the viability, invasiveness, and angiogenic potential of high-risk neuroblastoma (NB). In vitro assays were performed using NB cell lines SK-N-AS (non-MYCN-amplified) and SK-N-BE(2) (MYCN-amplified). The role of peroxisome proliferator-activated receptor gamma (PPARγ) was evaluated using the antagonist GW9662, gene expression (RT-qPCR), and protein levels (Western blot). In vivo, zebrafish xenografts were used to evaluate tumor size, angiogenesis, and caudal cell dissemination. I₂ supplementation significantly decreased cell viability in both cell lines, independent of PPARγ activation. In SK-N-BE(2), I₂ impaired cell migration, as measured by a wound-healing assay, in apparent independence of PPARγ activation. However, gene expression indicates that I₂ acts in complex ways, including direct antioxidant effects and PPARγ-mediated effects. The significant decrease in reactive oxygen species levels (DCFDA staining) and the silencing of the long noncoding RNA myocardial infarction-associated transcript (MIAT) by I₂ were directly associated with decreased MYCN and TrkB expression. In contrast, PPARγ activation was accompanied by overexpression of FasN and TrkA and a significant decrease in Aurka, a MYCN-stabilizing protein. In zebrafish, I₂-pretreated SK-N-BE(2) xenografts exhibited a clear reduction in angiogenesis (vascular density) and a decrease in invasive capacity. In conclusion, I₂ supplementation decreases cell viability and attenuates invasion and angiogenesis in NB cells, highlighting its potential as an adjuvant to conventional therapy for high-risk NB.

CLEC3B (C-type lectin domain family 3 member B), also known as tetranectin (TN), is a secreted trimeric protein containing a C-type lectin-like domain (CTLD). Located on chromosome 3p21.31. CLEC3B maintains organismal homeostasis through roles in immune regulation, angiogenesis, and musculoskeletal biology. Genetic studies demonstrate that CLEC3B deficiency impairs tissue repair, bone mineralization, and fibrinolytic balance. Altered CLEC3B expression is linked to cardiovascular disease progression, autoimmune susceptibility, and cancer prognosis. This review synthesizes CLEC3B's biological functions and evaluates its translational potential: circulating CLEC3B as a prognostic and diagnostic biomarker; tissue-resident CLEC3B as a predictive marker for therapeutic response; and CLEC3B-related pathways as candidate therapeutic targets for potential amenable to replacement or inhibition strategies. We identify critical research gaps to guide future investigations, including limited structural data, ambiguous glycan specificity, incomplete proteolytic network mapping, and lack of validated disease models. Collectively, these gaps currently preclude definitive therapeutic claims.

Ring finger protein 126 (RNF126) is a RING-type E3 ubiquitin ligase that has recently emerged as a multifaceted regulator of cellular homeostasis, stress adaptation, and disease progression. Through its structurally distinct zinc-finger and catalytic RING domains, RNF126 orchestrates substrate recognition and ubiquitin transfer, generating diverse ubiquitin linkages with both proteolytic and nonproteolytic functions. Initially characterized as a component of the protein quality control (PQC) machinery, RNF126 cooperates with chaperones such as BAG6 and UBQLN1 to eliminate mislocalized and misfolded proteins, thereby maintaining proteostasis. Beyond PQC, RNF126 plays pivotal roles in DNA damage response pathways by regulating homologous recombination, non-homologous end joining, checkpoint signaling, and genome stability through substrates, including MRE11, Ku80, RNF168, and 14-3-3σ. Genetic studies have further demonstrated its importance in embryogenesis and male fertility, and accumulating evidence has identified RNF126 as a critical driver of malignancy in multiple cancers. RNF126 promotes tumor progression by degrading or modulating key regulators, such as p21, PTEN, p53, PDKs, and LKB1, thereby enhancing proliferation, metabolic reprogramming, anoikis resistance, metastasis, and chemo/radioresistance. Intriguingly, RNF126 exhibits context-dependent functions, acting as an oncogene or tumor suppressor depending on the tissue type and substrate selection. In addition to cancer, RNF126 has been implicated in neurodegeneration, cardiac pathology, antiviral immunity and adaptive immune regulation. This review summarizes the current knowledge of RNF126 structure, ubiquitin signaling mechanisms, physiological functions, and pathological roles, while discussing emerging therapeutic strategies and future challenges for targeting RNF126 in precision medicine.

TERT, the catalytic subunit of telomerase, is aberrantly activated in most cancers and represents an attractive therapeutic target. However, conventional TERT-targeting strategies, including chemical inhibitors and siRNA, are limited by several issues, such as insufficient efficacy and off-target effects. In this study, we investigated whether dCas9-KRAB-mediated CRISPR interference (CRISPRi) could overcome the limitations by transcriptional repression of TERT without DNA cleavage. We first assessed the efficacy of the dCas9-KRAB system by applying it to H1299 non-small-cell lung cancer cells and observed reduction in TERT expression up to approximately 80% and significant decreases in cell viability and growth. Transcriptome-wide analysis showed limited detectable changes in non-target-gene expression under the conditions tested. Together, the results suggest that dCas9-KRAB-mediated CRISPRi could serve as a proof-of-principle approach for targeted repression of TERT in cancer cells with limited detectable effects on non-target-gene expression.

The multifaceted oncogenic role of teratocarcinoma-derived growth factor 1 (TDGF1) in colon cancer remains incompletely understood. Through integrative bioinformatic and functional analyses, we identified a novel competing endogenous RNA (ceRNA) axis wherein the long non-coding RNA OLMALINC directly sponges hsa-miR-3614-5p, leading to the derepression of TDGF1. This OLMALINC/miR-3614-5p/TDGF1 axis promoted colon cancer cell proliferation, migration, invasion, and anti-apoptosis in vitro, whereas TDGF1 knockdown significantly suppressed tumor growth in vivo. Mechanistically, TDGF1 co-activated oncogenic signaling via the Thr88-dependent Nodal/Smad2 cascade and the Glypican-1-mediated MAPK/AKT pathway. Beyond cell-autonomous effects, transcriptomic and single-cell analyses revealed that elevated TDGF1 correlates with an immunosuppressive microenvironment, characterized by reduced immune infiltration and altered LGALS9-CD44 malignant-T cell communication. Clinically, high TDGF1 expression in a tissue microarray cohort was significantly associated with advanced T stage, reduced expression of specific mismatch repair proteins (MLH1/PMS2), and poor overall survival. Collectively, this study delineates the OLMALINC/miR-3614-5p/TDGF1 regulatory circuit and establishes TDGF1 as a multifaceted driver of tumor progression, highlighting its potential as a prognostic biomarker and therapeutic target in colon cancer.

Ferroptosis, an iron‑dependent form of programmed cell death, is a promising target for cancer therapy. Peptidyl‑prolyl cis/trans isomerase 1 (PIN1), a member of the peptidyl‑prolyl cis/trans isomerase family, is often overexpressed in cancer and contributes to tumor cell proliferation, survival and metastasis. The present study investigated whether PIN1 regulates ferroptosis in gastric cancer (GC). GC cell models with either PIN1 knockdown or overexpression were established and treated with the ferroptosis inducer erastin, followed by assessment of cell viability and proliferation rate using Cell Couting Kit‑8 and colony formation assays, detection of PIN1 and cytoplasmic polyadenylation element binding protein 1 (CPEB1) expression via western blotting and reverse transcription‑quantitative PCR, and evaluation of glutathione peroxidase 4 (GPX4) expression through immunofluorescence assay. Experimental results indicate that PIN1 depletion increases erastin‑induced ferroptosis, as evidenced by increased levels of reactive oxygen species, malondialdehyde and intracellular free iron. PIN1 overexpression attenuates the erastin‑induced ferroptotic response, as evidenced by decreased levels of ferroptosis‑related biomarkers. Further analysis reveals that silencing PIN1 upregulates CPEB1, which, in turn, suppresses GPX4 expression. Simultaneous knockdown of CPEB1 reverses the ferroptosis‑enhancing effect of PIN1 depletion. These mechanistic findings suggest that PIN1 promotes GPX4 expression by repressing CPEB1, thus inhibiting Erastin‑induced ferroptotic cell death in GC. In vivo experiments further suggest that PIN1 knockdown significantly reduces the tumorigenic potential of GC cells. A novel PIN1‑CPEB1‑GPX4 axis was identified, in which PIN1 downregulates CPEB1 to mediate ferroptosis resistance. This axis represents a potential therapeutic target, as PIN1 knockout demonstrates significant tumor suppression in animal models. The present study identifies a novel PIN1‑CPEB1‑GPX4 regulatory axis that controls ferroptosis, suggesting its potential as a therapeutic target for advanced GC.