Pazopanib, a first-line tyrosine kinase inhibitor for advanced renal cell carcinoma (RCC), faces significant clinical limitations due to acquired resistance. In this study, we reveal a novel mechanism underlying pazopanib resistance in RCC, driven by a senescence-like phenotype without cell-cycle arrest. Transcriptomic profiling identified ALYREF as a key upregulated m5C reader in pazopanib resistant cells. Mechanistically, ALYREF stabilizes CCNA1 mRNA via m5C modification, promoting Cyclin A1 expression. The Cyclin A1-CDK2 complex phosphorylates p21 at Thr-57, inducing its cytoplasmic translocation and abrogating its inhibitory effect on cell cycle progression, thereby facilitating G1-S transition. Our findings uncover a critical ALYREF-Cyclin A1-p21 axis in RCC and suggest that targeting this pathway may provide novel therapeutic strategies to overcome pazopanib resistance.

Protein S-palmitoylation, the reversible thioesterification of cysteine side chains, is emerging as a druggable post-translational modification that couples membrane topology to oncogenic, metabolic, immune, and epigenetic networks in cancer. ZDHHC palmitoyltransferases and depalmitoylating enzymes, including acyl-protein thioesterases and palmitoyl-protein thioesterase 1, constitute a dynamic circuitry that governs the localization, stability, and signaling competence of key regulators of tumor growth, metabolic adaptation, and immune phenotype. Here, we synthesize recent structural and chemical biology advances that clarify how human ZDHHC enzymes achieve acyl-chain recognition and substrate engagement. Structural studies show that these enzymes adopt a four-transmembrane, "tent-like" fold, in which the helices create a membrane-embedded cavity for acyl-chain accommodation. We also discuss how ankyrin-repeat domains and accessory partners shape substrate recruitment and subcellular localization, and we highlight emerging high-throughput platforms that enable quantitative profiling of isoform- and site-selective modulators. We then discuss how ZDHHC-substrate circuits rewire canonical growth-factor signaling and epithelial-mesenchymal transition programs, metabolic and ferroptotic control nodes, innate immune sensing, and chromatin-linked regulation. These convergent mechanisms position ZDHHC-mediated S-palmitoylation as a context-dependent regulator of tumor progression, therapy response, ferroptosis sensitivity, and immune phenotype. Finally, we outline a translational framework encompassing clinical-stage PPT1 inhibitors, selective ABHD17 blockade, emerging ZDHHC modulators, substrate-competitive strategies targeting checkpoint palmitoylation, and selected comparator approaches affecting Wnt and Hedgehog ligand lipidation. Current evidence positions ZDHHC-mediated S-palmitoylation as a regulatory layer with potential biomarker and therapeutic relevance; however, not all reported ZDHHC-substrate associations carry equivalent evidentiary weight. Mechanisms supported by convergent site-directed, genetic, biochemical, functional, and in vivo evidence should be distinguished from associations inferred mainly from expression profiling, overexpression systems, single-model observations, or broad pharmacological perturbation. Clinical translation remains preliminary and is constrained by isoform selectivity, substrate redundancy, incomplete pharmacodynamic read-outs, and the absence of validated biomarker-guided patient stratification.

Synaptotagmin-binding cytoplasmic RNA-interacting protein (SYNCRIP) is an RNA-binding protein (RBP) implicated in the pathogenesis of various cancers through involvement in regulating multiple cellular processes. Notably, this study identified that SYNCRIP expression is significantly elevated in glioblastoma (GBM) and is associated with poor prognosis and tumor progression. Mechanistically, SYNCRIP upregulates SIRT1 expression at both the transcriptional and post-transcriptional levels by stabilizing SIRT1 mRNA. Meanwhile, loss of SYNCRIP leads to reduced SIRT1 expression, accumulation of reactive oxygen species (ROS), and induction of ferroptosis. Notably, restoration of SIRT1 rescues cells from ferroptotic cell death, supporting the critical role of SIRT1 in SYNCRIP-mediated ferroptosis resistance. SYNCRIP also enhances hexokinase 2 (HK2) expression through transcriptional activation and internal ribosome entry site (IRES)-mediated translation, thereby promoting glycolytic activity in GBM. Furthermore, depletion of SYNCRIP results in mitochondrial dysfunction and impairs GBM cell migration and invasion by downregulating epithelial-mesenchymal transition (EMT)-associated factors. Collectively, these findings suggest that SYNCRIP is a key regulator of GBM progression by maintaining metabolic homeostasis and ferroptosis resistance, highlighting SYNCRIP as a potential therapeutic target in GBM.

Glioblastoma (GBM), the most common and aggressive primary brain tumor, exhibits profound metabolic reprograming that sustains its progression and therapy resistance. Our previously published work demonstrated that C3G expression is downregulated in GBM, which enhances migration and invasion. Here, we show that C3G silencing or knockout in GBM cells reprograms glucose metabolism favoring glycolysis and lactate production through upregulation of PKM2 and LDHA. Furthermore, Seahorse metabolic profiling further revealed increased respiratory capacity and glycolysis upon C3G downregulation or depletion. Mechanistically, C3G silencing increases the levels of the splicing factor PTBP1, which forces PKM splicing towards PKM2 expression as demonstrated by transient PTBP1 silencing, although other splicing factors such as SRSF3 could also contribute to PKM2 expression. Additionally, C3G downregulation or depletion enhances sphere formation, stemness and tumor initiating capacity in GBM cells, which is rescued by C3G re-expression in C3G knockout GBM cells. This enhanced stemness induced by C3G silencing in GBM cells is prevented by transient PTBP1 or PKM2 silencing or pharmacological inhibition of PKM2 with compound 3K, which also decreases cell viability within the spheres (3D-cell cultures) and the expression of stemness markers. However, in 2D-cell cultures compound 3K increases cell viability in C3G-silenced GBM cells, while decreasing that of C3G knockout cells. This supports a specific role for C3G/PKM2 axis in GBM cancer stem cells through mechanisms likely dependent on both PKM2-mediated metabolic reprogramming and nuclear effects on gene transcription. Altogether, our findings identify C3G as a novel regulator of GBM metabolism and stemness acting through PKM2, unveiling new potential diagnostic and therapeutic implications for C3G in a subset of GBM patients.

Tumor-immune cell interactions critically contribute to the progression of non-small cell lung cancer (NSCLC). In this study, we investigated the role of WNT1-inducible signaling pathway protein 3 (WISP-3) in regulating tumor cell adhesion and the underlying molecular mechanisms in lung adenocarcinoma cells. Treatment with recombinant WISP-3 significantly increased intercellular adhesion molecule-4 (ICAM-4) expression at both mRNA and protein levels in A549 and H1299 cells in a dose-dependent manner. Consistently, WISP-3 enhanced tumor-monocyte adhesion, indicating its involvement in tumor-immune cell interactions. Mechanistically, WISP-3 stimulated rapid activation of the MEK/ERK signaling cascade, as demonstrated by increased phosphorylation of MEK and ERK. Pharmacological inhibition of MEK using PD98059 or U0126, as well as direct inhibition of ERK with SCH772984, markedly attenuated WISP-3-induced ICAM-4 expression and THP-1 adhesion. These findings were further supported by siRNA-mediated knockdown of MEK or ERK, confirming the essential role of this pathway. In addition, WISP-3 suppressed the expression of hsa-miR-12131, which was identified as a negative regulator of ICAM-4. Restoration of hsa-miR-12131 significantly reduced ICAM-4 expression and impaired tumor-monocyte adhesion, indicating that miR-12131 functions downstream of MEK/ERK signaling. Collectively, these results demonstrate that WISP-3 promotes ICAM-4-dependent monocyte adhesion through activation of the MEK/ERK pathway and subsequent suppression of hsa-miR-12131. This WISP-3/MEK/ERK/miR-12131/ICAM-4 axis provides new insight into tumor-immune interactions in NSCLC and highlights potential therapeutic targets.

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) selectively induces apoptosis in cancer cells. However, many cancer cells are resistant to TRAIL because of downregulation of death receptors (DRs) and overexpression of anti-apoptotic proteins. Ubiquitin-conjugating enzyme E2N (UBE2N), also known as Ubc13, plays a central role in ubiquitin-mediated cellular activities. In this study, we aimed to explore the sensitization effect of UBE2N inhibition in TRAIL-mediated apoptosis in cancer cells. NSC697923 (a potent inhibitor of UBE2N) alone and TRAIL alone did not induce apoptosis in renal carcinoma Caki cells. However, combined treatment with NSC697923 and TRAIL significantly enhanced apoptotic cell death in cancer cells, but not in normal cells. Mechanistically, NSC697923 induced upregulation of DR5 mRNA and protein levels through CHOP-mediated DR5 transcriptional activation and ubiquitin-mediated DR5 stabilization. NSC697923-mediated DR5 mRNA upregulation was regulated by upregulation of CHOP expression, a key transcriptional factor of DR5. CHOP siRNA treatment inhibited NSC697923-mediated DR5 protein expression. Moreover, NSC697923 generated ROS, and pretreatment with ROS scavengers inhibited DR5 upregulation and NSC697923 plus TRAIL-mediated cell death. These findings suggest that UBE2N inhibitor enhances TRAIL-induced apoptosis by DR5 upregulation and UBE2N inhibition may serve as a potential strategy to overcome TRAIL resistance in cancer therapy.

Breast cancer is the second most common cancer worldwide and remains the leading cause of cancer-related deaths among women. Triple-negative breast cancer (TNBC) represents approximately 15-20% of all breast cancer cases and is characterized by an aggressive clinical course and a high risk of metastasis. Extracellular signal-regulated kinase 5 (ERK5) is a critical biomarker that promotes tumor progression through mechanisms involving cell proliferation, invasion, and metastasis; however, its precise role in epithelial-mesenchymal transition (EMT) in TNBC remains unclear. In this study, we analyzed data from 117 patients with TNBC and found that high ERK5 expression was significantly associated with tumor progression, shorter progression-free survival, and shorter overall survival. RNA sequencing of a highly metastatic TNBC cell line revealed that ERK5 knockdown modulated the expression of various gene clusters, particularly those associated with DNA repair, G2/M checkpoint regulation, and angiogenesis. In addition, ERK5 knockdown in a mouse xenograft model significantly suppressed tumor proliferation and lung metastasis, inhibited tumor cell migration, and reduced the expression of EMT-related proteins. Mechanistically, our data further demonstrated that ERK5 regulates the interaction between cellular JUN (c-JUN) and the vimentin promoter, thereby modulating vimentin expression and downstream signaling pathways. A significant positive correlation between ERK5 and vimentin expression in human TNBC tissue specimens further supported this regulatory association. These findings suggest that ERK5 mediates the recruitment of c-JUN to regulate vimentin expression, thereby promoting EMT and metastasis. Thus, the ERK5/c-JUN/vimentin axis may be a potential therapeutic target to improve clinical outcomes in patients with TNBC.

Oral squamous cell carcinoma (OSCC) frequently metastasizes, leading to poor patient outcomes. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) has been implicated in cancer progression; however, the downstream mechanism driving OSCC motility remains incompletely defined. Cyr61 expression was elevated in OSCC and associated with advanced clinicopathological features. In OSCC cell lines, recombinant Cyr61 enhanced wound closure and Transwell migration and increased intercellular adhesion molecule-1 (ICAM-1) expression at both the mRNA and protein levels. ICAM-1 silencing significantly attenuated Cyr61-induced cell motility, indicating that ICAM-1 is an important downstream effector. Mechanistically, Cyr61 signaling was initiated through integrin αvβ3 and αvβ5, as neutralizing antibodies and siRNAs targeting these integrins suppressed Cyr61-induced migration and ICAM-1 expression. Cyr61 also induced phosphorylation of PLC, PKC, and c-Src, and pharmacological or siRNA-mediated inhibition of these kinases attenuated ICAM-1 upregulation and cell migration. Moreover, Cyr61 enhanced AP-1 activity via c-Jun phosphorylation, increased c-Jun occupancy at the ICAM-1 promoter, and inhibition of AP-1 signaling diminished Cyr61-driven ICAM-1 expression and motility. Together, these data define an integrin αvβ3/αvβ5-PLC-PKC-c-Src-AP-1 axis that transcriptionally upregulates ICAM-1, promoting OSCC migration and providing a mechanistic basis for targeting Cyr61-driven migratory programs in OSCC.

Arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is a critical post-translational modification that modulates gene expression and signal transduction. Although the involvement of PRMTs in malignancy is increasingly recognized, a comprehensive pan-cancer synthesis of this family remains elusive. We sought to elucidate the multi-omic landscape of PRMTs and define their biological contributions to colorectal cancer (CRC) progression.

Avian leukosis virus (ALV) remains a major threat to the poultry industry due to its ability to establish persistent infection, induce immunosuppression, and promote tumorigenesis. Despite progress in eradication programs, effective control is hindered by subclinical infection, vertical transmission, and rapid viral evolution. A key limitation lies in the complexity of host-virus interactions, which are governed by multi-layered regulatory processes that cannot be fully resolved by studies focusing on single genes, pathways, or omics layers. In addition, the lack of robust and dynamic phenotypic indicators further constrains the dissection of resistance mechanisms. Recent advances in multi-omics technologies provide an opportunity to overcome these challenges by capturing coordinated changes across genomic, transcriptional, proteomic, and epigenetic levels. Integrating these data with molecular phenotypes, such as expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs), enables the linking of genetic variation to functional immune responses. Furthermore, CRISPR-based functional screening offers a systematic approach for validating candidate host factors and identifying key regulators of viral replication and immune modulation. In this review, we summarize the epidemiology and molecular biology of ALV, outline current understanding of host-virus interaction networks with an emphasis on innate immune responses, and highlight how integrative multi-omics combined with functional genomics can advance the identification of critical host determinants. This framework provides a systems-level perspective for deciphering ALV-host interactions and supports the development of more effective antiviral strategies.

Ectopic hepatocellular carcinoma (EHCC) is an exceedingly rare malignancy characterized by its occurrence outside the liver without a detectable intrahepatic primary tumor. Owing to its rarity and the absence of standardized management guidelines, the diagnosis and treatment of EHCC pose significant challenges.

Colorectal cancer (CRC) with microsatellite-stable (MSS)/pMMR status resists immune checkpoint blockade due to its immunologically "cold" tumor microenvironment. We developed Lipo-LPS-Rg3, a dual-functional nanoliposome co-delivering lipopolysaccharide (LPS) and ginsenoside Rg3, to simultaneously ignite pyroptosis and attenuate PD-L1-associated immune suppression. LPS triggered GSDMD-mediated pyroptosis, releasing DAMPs and recruiting CD8+ T cells, while Rg3 reduced PD-L1 expression in vitro, at least partly by inhibiting NFATc1 nuclear translocation. In vivo, Lipo-LPS-Rg3 decreased PD-L1 protein expression in tumor tissues and promoted both CD8+ T-cell infiltration and IFN-γ-producing effector function. The nanoplatform achieved tumor-targeted delivery, induced near-complete regression in colorectal cancer, and exhibited minimal systemic toxicity. By converting "cold" tumors into "hot" and supporting antitumor T-cell activity, Lipo-LPS-Rg3 offers a promising strategy for MSS/pMMR CRC immunotherapy.

ObjectiveTo investigate whether naringin enhances the chemosensitivity of nasopharyngeal carcinoma-derived CNE2 cells to paclitaxel and identify potential molecular mediators.MethodsCNE2 cells were treated with naringin alone or in combination with paclitaxel, cisplatin, or 5-fluorouracil. Cell viability, proliferation, and migration were assessed using cell counting kit-8 and Transwell assays. Transcriptomic profiling followed by bioinformatic analysis of Gene Expression Omnibus datasets (GSE53819, GSE12452, and GSE102349) was performed to identify nasopharyngeal carcinoma prognosis-related genes. AKR1C3 overexpression was established via lentiviral transduction, and pharmacological inhibition was performed using ASP9521. mRNA and protein expression were validated using reverse transcription quantitative polymerase chain reaction and Western blot analysis.ResultsNaringin (160 μM) demonstrated a trend toward reducing the half-maximal inhibitory concentration of paclitaxel from 10.52 to 8.04 nM; however, it did not significantly alter sensitivity to cisplatin or 5-fluorouracil. Combined treatment with 2 nM paclitaxel and 160 μM naringin synergistically suppressed CNE2 proliferation and migration compared with that using either agent alone (p < 0.05). Bioinformatic analysis revealed that high AKR1C3 expression was correlated with improved survival in patients with nasopharyngeal carcinoma (p < 0.05), whereas high PAIP1, PRKDC, PTPRR, and COL12A1 expressions were correlated with poorer outcomes. Reverse transcription quantitative polymerase chain reaction confirmed that both naringin and paclitaxel upregulated AKR1C3 mRNA, with the combination producing the strongest effect. Gain-of-function studies demonstrated that AKR1C3 overexpression significantly enhanced paclitaxel sensitivity, with half-maximal inhibitory concentration values decreasing from 13.63 to 6.994 nM in CNE2 cells and from 8.534 to 4.668 nM in CNE1 cells. Furthermore, the specific AKR1C3 inhibitor, ASP9521, significantly attenuated the synergistic anti-proliferative and anti-migratory effects of paclitaxel + naringin in CNE2 cells, confirming that naringin enhances chemosensitivity to paclitaxel by upregulating AKR1C3 expression.ConclusionsNaringin sensitizes CNE2 cells to paclitaxel, potentially via AKR1C3 upregulation. This flavonoid may represent a low-toxicity adjunct to enhance the efficacy of paclitaxel in nasopharyngeal carcinoma.

Nucleoporin 98 rearrangements (NUP98re) occur in a wide range of hematologic malignancies including acute leukemias with a variety of fusion partners. NUP98re is associated with adverse prognosis, especially in children. We aimed to better understand the genomics of acute leukemias with NUP98re including fusion partners and co-occurring genomic alterations (GA). Results from 5905 patients with acute leukemia undergoing standard-of-care next generation sequencing on FoundationOneHeme were included for analysis. A total of 78 (1.3%) patient samples harbored NUP98re with a median age of 19 years compared with 62 years for the cases with no NUP98 rearrangement (NUP98wt) (p < 0.001). Patients with NUP98re were more frequently of admixed American ancestry (p < 0.001). Among patients with acute myeloid leukemia, individual genomic alterations more frequently identified in NUP98re cases included WT1 (77% vs. 11%, p < 0.001) and FLT3 (49% vs. 26%, p < 0.001); Alterations more frequent in the NUP98wt cohort included NPM1, KMT2A, TET2, DNMT3A, ASXL1, SRSF2, STAG2, and BCOR (all p < 0.05). NUP98re are rare in patients with acute leukemia, more frequent in pediatrics and younger adults but distributed across all age groups. NUP98re is associated with a unique genomic landscape featuring increased frequencies of mutations with proliferative features (FLT3 and KRAS) and growth suppression (WT1). Alterations in WT1 had the highest co-occurrence rate in samples containing NUP98re. This work highlights the unique GA associated with NUP98 and emphasizes the need for clinical studies to reveal underlying biologic mechanisms and enhance optimal management in the presence of potentially targetable alterations such as NUP98re.

This study preliminarily examines the clinical value and molecular mechanisms of LINC00511 in breast cancer (BRCA) through bioinformatics analysis.

Colorectal cancer (CRC) commonly evolves through precursor adenomatous polyps; however, reliable non-invasive biomarkers capable of distinguishing benign from malignant colorectal lesions remain limited. Circulating microRNAs have emerged as promising molecular indicators of tumour initiation and progression.

Cholangiocarcinoma (CCA) is an aggressive biliary malignancy usually diagnosed at advanced stages because early symptoms are vague. Conventional serum markers, including carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), have limited sensitivity and specificity. Circulating cell-free DNA (cfDNA), particularly ALU-115, ALU-247 and DNA integrity index, may provide improved diagnostic accuracy by reflecting tumor-derived DNA fragmentation.

Compare the treatment efficacy of EGFR TKIs in patients with non-small cell lung cancer with the EGFR L858R exon 21 mutation.

Breast cancer is a heterogeneous disease consisting of molecular subtypes with varying aggressiveness, growth rates, and therapeutic responses. MicroRNAs (miRNAs) hold potential as biomarkers owing to their role in gene expression regulation in cancer, as well as their specificity and stability in clinical samples. The mapping of miRNAs associated with disease recurrence and progression in each breast cancer subtype remains limited. This scoping review aimed to map the scientific literature on miRNAs related to recurrence and disease progression in TNBC, luminal, and HER2+ breast cancer subtypes.

Breast cancer stem cells (BCSCs) are responsible for chemotherapy resistance, metastasis, and tumor recurrence. Paclitaxel-primed mesenchymal stem cells (MSCs) can activate T cells, offering a novel immunotherapeutic approach. However, the molecular mechanisms underlying BCSC-immune interactions remain poorly understood.