Glioblastoma (GBM) is a highly aggressive and therapy-resistant brain tumor, necessitating innovative multi-target strategies. Natural compounds like the triterpenoid Alisol B from Alisma orientale hold promise due to their polypharmacological potential, yet their system-level mechanisms are unclear. Using an integrated multi-omics approach (transcriptomics, proteomics, lysine acetyl-proteomics) in resistant GBM cells and validating findings in vitro and in AB strain zebrafish (Danio rerio) xenografts, we found that Alisol B induces endoplasmic reticulum stress and G2/M arrest, initiated by extensive lysine acetylation reprogramming on histones and metabolic enzymes (e.g., FASN, FDFT1). This epigenetic rewiring leads to disrupted cholesterol biosynthesis, characterized by transcriptional activation of the mevalonate pathway alongside post-transcriptional suppression of terminal enzymes (DHCR7, CYP51A1), suggestive of toxic intermediate accumulation. Alisol B also downregulated the oncogenic axis (BIRC5-FOXM1-ITGA4) and SCD5. This study delineates Alisol B's novel multi-mechanistic action through concurrent epigenetic rewiring, metabolic dysfunction induction, and survival network dismantling. Our work elucidates the molecular pharmacology of a natural compound and provides a framework for developing polypharmacological therapies against resistant cancers, exemplifying natural products as tools to reveal new therapeutic paradigms.

This study utilized network pharmacology, bioinformatics, along with machine learning to investigate the multi-target synergistic anti-cancer mechanisms of three edible medicinal plants (EMPs)-mulberry leaf, lotus leaf, and sea buckthorn-against oral and esophageal squamous cell carcinomas (OSCC and ESCC). We identified potential active constituents and their targets through mining Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Swiss Target Prediction databases. Concurrently, integration with differential expression profiles and co-expression modules identified crucial intersection targets between the EMPs and these two cancers. Subsequent machine learning algorithms and cross-cancer analysis consistently identified Matrix Metalloproteinase-1 (MMP1) as a critical hub gene. Its overexpression is closely associated with tumor invasion and metastasis. Molecular simulations revealed stable binding interactions between active constituents from three EMPs and hub proteins. Furthermore, research on immune cell infiltration suggested that the active components of three EMPs may impact the tumor immune microenvironment in both OSCC and ESCC through the regulation of pivotal gene expression. Collectively, this work systematically elucidates the molecular basis underlying the multi-target, multi-pathway synergistic anti-cancer effects of these EMPs, providing a theoretical foundation for developing natural drugs against these squamous cell carcinomas.

Several receptors have received considerable attention as therapeutic targets in gastric cancer (GC), and numerous receptor inhibitors have been developed. However, the development of novel gastric cancer therapeutics is time-consuming. Therefore, this study aimed to identify drugs effective against gastric cancer from existing anticancer agents originally developed for other malignancies. In this study, the cancer-related genomic profiles of 286 genes were analyzed in 14 gastric cancer cell lines using targeted DNA sequencing, and these cell lines were utilized as models to evaluate the efficacy of 35 anticancer drugs. The 14 cell lines were assessed for 286 gene alterations, copy number variations, amplification of 14 gastric cancer-related therapeutic targets, and sensitivity to 35 drugs. p-MET and MET were overexpressed in the SNU5, SNU620, MKN45, and Hs746T cell lines, while p-EGFR was overexpressed in the NCI-N87 cell line. FGFR2 overexpression was observed in the Kato III and SNU16 cell lines. TGFβR1 was overexpressed in the MKN7 cell line. HER2 and CDK12 were overexpressed in the NCI-N87 and MKN7 cell lines. PD-L1 overexpression was detected in the Hs746T and MKN7 cell lines. CD44 was overexpressed in the SNU5 and Hs746T cell lines and CLDN18 overexpression was observed in the MKN7 cell line. Well-characterized gastric cancer cell lines are essential for drug development research. This study provides a framework for selecting cell lines that are responsive to each of the 35 anticancer drugs and elucidating their underlying therapeutic mechanisms through follow-up studies. Ultimately, clinical studies are required to confirm the therapeutic efficacy of the selected drugs.

Proanthocyanidins (PAs) display antioxidant properties and can partially delay pericarp browning in postharvested litchi (Litchi chinensis Sonn.) fruits. In this study, litchi fruit was treated with 3 g/L PA and then stored at 25 °C for 10 days. Differential metabolites and differentially expressed genes were comprehensively analyzed in litchi pericarp across four stages of browning progression. A total of 630 metabolites were identified through untargeted metabolomic analysis, with 237 of them being annotated in the kyoto encyclopedia of genes and genomes (KEGG) database. The abundance of flavonoids (kaempferol), six types of anthocyanins, cyanidins, (-)-epicatechin, and (+)-catechin in the PA biosynthetic pathway was notably reduced in PA-treated pericarp compared to that of the control fruit. Transcriptomic analysis also revealed that five genes in the phenylpropanoid biosynthesis pathways and seven genes of phenoloxidase were significantly downregulated. In addition, correlation analysis revealed significant positive correlations between the browning index and genes like LcFLS (flavonol synthase), LcANS (anthocyanidin synthase), LcUFGT (UDP-glucose:anthocyanidin 3-O-glucosyltransferase), LcPPO (polyphenol oxidase), and LcLAC7 (laccase), and a significant negative correlation with PAs and (-)-epicatechin. In conclusion, PA treatment can efficiently delay pericarp browning, mainly by reducing brown substrate accumulation and oxidation, and decreasing PA oxidation and polymerization. This study delves into the regulatory mechanisms through which PA delays litchi pericarp browning.

Glycogen synthase kinase 3 (GSK3/SHAGGY-like kinase) plays a pivotal role in regulating plant growth, development, and stress responses. To elucidate the characteristics of the GSK family in Glycine max, this study employed whole-genome data combined with bioinformatic and gene expression analyses to investigate the gene structure, chromosomal localization, collinearity, phylogenetic evolution, promoter cis-elements and differential gene expression analysis. Additionally, the expression patterns of GmGSK genes under manganese (Mn) stress and their associated phenotypic alterations were analyzed. A total of 22 GmGSK family members were identified, all harboring the characteristic GSK kinase domain. These members are distributed across 16 chromosomes, encoding proteins ranging from 380 to 802 amino acids (aa) in length. Phylogenetic analysis classified the GmGSK family into four evolutionary clades, consistent with patterns observed in Arabidopsis and Oryza sativa. Members within the same clade share identical exon-intron structures and conserved motifs. Collinearity analysis revealed that segmental duplication events have been crucial in the functional expansion of the GmGSK family through intraspecific collinearity. In recent years, alongside industrial development and fertilizer imbalance, the effective manganese concentration in agricultural soils has risen abnormally in some regions of China, leading to toxic effects on crops. Soybean, an oilseed crop relatively sensitive to manganese, has been adversely impacted. Clarifying the response mechanisms of soybean seedlings to manganese stress is therefore of significant importance for improving both yield and quality. Manganese stress treatment induced significant up-/down-regulation of specific GmGSK members in soybean, concomitant with pronounced inhibition of root elongation and leaf growth. This study provides a theoretical framework for deciphering the molecular regulatory mechanisms by which the GmGSK gene family mediates plant responses to Mn stress, offers insights into soybean Mn tolerance mechanisms, and establishes a foundation for genetic improvement of Mn-tolerant traits in crops.

Plants are frequently exposed to various abiotic stresses during their growth and development. S. portulacastrum possesses inherent tolerance to salinity and heavy metals, yet the underlying molecular mechanisms remain poorly understood. In this study, we performed a comprehensive analysis of S. portulacastrum by integrating full-length transcriptome sequencing and RNA sequencing (RNA-seq) under salt stress conditions. Transcriptome analysis identified 2839 and 1813 DEGs in leaves and 7328 and 754 DEGs in roots at 7 and 14 ds after NaCl treatment, respectively. Pathway enrichment analysis indicated that these DEGs were significantly enriched in pathways associated with Photosynthesis, plant hormone signal transduction, Linoleic acid metabolism, chlorophyll metabolism, and amino acid metabolism. Expression profiling showed that JAZ subfamily genes were significantly upregulated in both leaves and roots under salt and Cd stress. We cloned SpJAZ1, SpJAZ5, and SpJAZ7, and generated their overexpression lines in Arabidopsis. Physiological assays demonstrated that overexpression of SpJAZ1, SpJAZ5, and SpJAZ7 reduced hydrogen peroxide content by 29.07%, 20.62%, and 19.79%, respectively, and lowered the reduction in chlorophyll content (0.12, 0.15, and 0.17 μg/mL vs. 0.22 μg/mL). Meanwhile, proline content was increased in these lines (2.34, 2.08, and 2.05 μg/mL vs. 1.53 μg/mL), alongside enhancements in root length, lateral root number, and water content under salt stress. Importantly, these overexpression lines displayed a similar functional trend under Cd stress. Collectively, our results reveal potential crosstalk between the JA signaling pathway and stress mitigation pathways in S. portulacastrum in response to salt and Cd stresses.

Ultraviolet (UV) exposure accelerates skin aging by inducing oxidative stress, extracellular matrix (ECM) degradation, and epidermal barrier dysfunction. This study investigated the protective effects of Brazilian pepper tree (SB), neem (SD), and Vietnamese coriander (PP) leaf extracts obtained by supercritical fluid extraction (SFE) using CO2 with ethanol as a co-solvent against radiation-induced cellular damage. Among these, SB yielded the greatest amount of extract and exhibited the highest levels of phenolic and flavonoid constituents, including naringin, epicatechin gallate, and rosmarinic acid. These compounds, identified through HPLC profiling, were associated with strong inhibition of collagenase, elastase, and hyaluronidase, and exhibited potent antioxidant activity in the DPPH assay. Under UVC-induced oxidative stress in HaCaT keratinocytes, SB markedly enhanced the mRNA expression of key genes involved in ECM integrity (COL1A1, 3.04 ± 0.15-fold), epidermal barrier and hydration (FLG, 4.66 ± 0.17-fold; HAS1, 1.90 ± 0.14-fold), and cellular defense mechanisms (SIRT1, 3.83 ± 0.54-fold), demonstrating superior efficacy to reference antioxidants (EGCG and ascorbic acid) in upregulating key barrier genes like FLG. Overall, the findings highlight SB as the extract with the most comprehensive photoprotective properties and support the use of SFE-derived botanical extracts as promising agents for natural and photoprotective skincare applications.

Prostate cancer (PCa) is the most general cancer in men and is often linked with distant metastasis in its later stages. The caffeic acid (CA) derivative, N-(4-methoxyphenyl)methylcaffeamide (MPMCA), demonstrates superior liver-protective effects compared to CA. Nevertheless, the functions of MPMCA on prostate cancer metastasis remain unclear. Here, we demonstrate that MPMCA blocks migration and invasion in prostate cancer cells without affecting cell viability. By suppressing the production of mesenchymal markers Vimentin, N-cadherin and β-catenin and upregulating the production of the epithelial marker Zonula Occludens-1 (ZO-1), MPMCA also controls Epithelial-Mesenchymal Transition (EMT). The Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway has been documented to regulate MPMCA-inhibited cell motility. Transfection with Snail and Slug cDNA reverses MPMCA's suppression of EMT, migration, and invasion in prostate cancer cells. Importantly, our in vivo data indicates that MPMCA reduces Snail and Slug expression and prostate cancer metastasis. Our evidence suggests that MPMCA is a novel therapeutic candidate for treating metastatic prostate cancer.

Antiepileptic drugs (AEDs) are primarily indicated for controlling epileptic seizures. However, accumulating clinical evidence suggests that their benefits in patients with central nervous system (CNS) tumors extend beyond seizure management. Emerging evidence indicates that AEDs possess direct antitumor activity independent of their antiepileptic effects, highlighting a promising novel direction for CNS tumor therapy. This review elucidates the multifaceted antitumor mechanisms of classic (e.g., valproic acid and levetiracetam) and novel (e.g., cannabidiol) AEDs, including their impacts on metabolic reprogramming, epigenetic regulation, endoplasmic reticulum stress and unfolded protein response (ERS-UPR), ion homeostasis, and the tumor immune microenvironment (TIME) to provide new insights and a theoretical basis for developing multitarget therapeutic strategies.

Fibrosis appears to be an out-of-control wound-healing response that drives a progressive formation of scar tissue in an organ. A key profibrotic cytokine, transforming growth factor beta-1 (TGF-β1), upregulates levels of the extracellular sialidase neuraminidase 3 (NEU3), and NEU3 in turn can activate latent TGF-β1 to release active TGF-β1 from the sequestering latency-associated peptide (LAP). In the mouse bleomycin model of pulmonary fibrosis, NEU3 is both necessary and sufficient for pulmonary fibrosis. In this report, we find that NEU3 protein levels increase both intracellularly and extracellularly in cultures of human lung fibroblasts within 5 min of TGF-β1 exposure. This effect is driven by an increase in translation and is independent of new transcription, supporting a model where TGF-β1 causes a pool of weakly translated NEU3 mRNA to increase translation. By participating in the feedback loop, latent TGF-β1 makes cells more sensitive to TGF-β1. LAP also stimulates NEU3 expression and acts synergistically with TGF-β1 to upregulate NEU3. The positive feedback loop is blocked by NEU3 inhibitors. The RNA helicase DEAD-box helicase 3 (DDX3) mediates NEU3 translation, and the DDX3 inhibitor RK-33 blocks the rapid upregulation of NEU3 by TGF-β1 and LAP. Exposure of cells to TGF-β1 but not LAP induces dephosphorylation of DDX3 within two minutes, suggesting that the mechanisms used by TGF-β1 and LAP to activate DDX3 to increase NEU3 levels may differ. Together, these results suggest that a rapid positive feedback loop involving TGF-β1, LAP, and NEU3 helps drive fibrosis.

Proteasome inhibitor (PI) resistance remains a major barrier in the treatment of multiple myeloma (MM), underscoring the urgent need to elucidate underlying mechanisms and identify actionable therapeutic targets. Here, we uncover METTL16 as a regulator of MM progression and PI sensitivity via an m6A methyltransferase activity-independent mechanism of translational control. Mechanistically, METTL16 overexpression is associated with altered PERK-eIF2α interaction and reduced eIF2α phosphorylation, accompanied by increased translation of key transcripts, including PSMB5 and CCND1. Consistently, these translational outputs coincide with increased proteasome activity and proliferative capacity. Notably, pharmacological targeting of METTL16 enhances the efficacy of multiple PIs in MM cells. These findings not only expand the functional landscape of METTL16 beyond RNA methylation, but also suggest that METTL16 represents a potential target for improving PI-based therapy in MM.

Osteosarcoma (OS) is a common malignant tumor which lacks robust biomarkers for prognosis and treatment stratification. This research aims to construct a predictive gene signature in OS with prognostic and therapeutic implications. We downloaded from TARGET-OS and GEO databases and obtained 298 differentially expressed genes (DEGs) by analysis of variance. The prognosis model, including multiple genes, was successfully constructed. We identified three molecular subtypes with distinct phenotypes, immune microenvironment profiles, and pathway enrichment patterns. The characteristics of the prognostic model included seven genes (FRZB, MX1, PTN, GRP, ITK, MYC, SERPINE2). Among these genes, SERPINE2 was prioritized for experimental validation; SERPINE2 knockdown suppressed osteosarcoma cell growth and invasion and increased cisplatin-induced DNA damage. Collectively, our results support an integrative prognostic model for OS and suggest SERPINE2 as a candidate modulator of tumor progression and cisplatin resistance.

Diffuse large B-cell lymphoma (DLBCL) presents a clinical challenge due to its high recurrence risk and therapeutic resistance driven by epigenetic factors. To address this gap, we developed CZ2 (N-(4-(1,3,2-dithiarsinan-2-yl)phenyl)-3-(benzo[d][1,3]dioxol-5-yl)acrylamide), a novel organic arsenical compound, and explored its therapeutic efficacy through a multimodal mechanistic approach in DLBCL.

Cholangiocarcinoma (CCA), an aggressive hepatobiliary malignancy with poor prognosis, involves abnormal molecular regulatory networks. This study explores α-1-microglobulin/bikunin precursor's (AMBP's) role in CCA, its pro-carcinogenic mechanisms via the wingless/integrated (WNT) pathway, and Huaier polysaccharide's targeted therapeutic potential. Using GSE132305, R software identified differentially expressed genes. Gene ontology/Kyoto encyclopedia of genes and genomes, gene set enrichment analysis, and Metascape analyzed enriched pathways, focusing on WNT. Weighted gene co-expression network analysis explored gene-phenotype correlations. STRING-based protein-protein interaction networks and algorithms (MCC, DMNC, and EPC) identified hub genes. TCGA enabled survival analysis and differential expression visualization. CIBERSORT analyzed immune infiltration (especially Tregs). TCMSP screened Huaier components, with molecular docking testing target binding. Reverse transcription quantitative polymerase chain reaction and Western blotting validated hub gene functions. Differentially expressed genes enriched in WNT, a key driver of CCA. Weighted gene co-expression network analysis and protein-protein interaction identified AMBP as a hub gene; its high expression linked to lower survival and elevated levels in CCA tissues. Increased Tregs in CCA correlated with immunosuppression and poor prognosis. Multi-omics confirmed AMBP promotes malignancy via WNT activation. Quercetin, Huaier main component, showed strong binding to AMBP via multiple interactions. AMBP overexpression in CCA cells activated WNT molecules (β-catenin, c-Myc, and Cyclin D1), enhancing tumor progression. Huaier targeted AMBP, reducing WNT activity and related proteins. High AMBP expression associates with CCA tumorigenesis, immunosuppression, and poor prognosis, acting via WNT. Huaier polysaccharide reverses CCA malignancy by inhibiting AMBP, reducing invasiveness/metastasis and improving prognosis.

Small cell lung cancer (SCLC), accounting for ~15% of lung cancers, is an aggressive and lethal tumor type. It is characterized by rapid proliferation, early metastasis, and poor prognosis. Current therapies, including platinum-based chemotherapy and recently introduced immune checkpoint inhibitors, provide modest survival benefits due to frequent relapse and therapeutic resistance. At the molecular level, SCLC is marked by near-universal loss of the tumor suppressors genes TP53 and RB1, and exhibits marked heterogeneity driven by several key master transcription factors. These factors define distinct molecular subtypes with unique gene expression programs and therapeutic vulnerabilities, enabling cell plasticity and subtype switching in response to treatment pressures. A thorough understanding of these subtype-specific dependencies and the epigenetic mechanisms regulating transcription is critical for developing effective and durable therapies. This review focuses on these aspects and evaluates the potential of epigenetic-targeted strategies in the treatment of SCLC.

Xylene is a common industrial solvent that includes three isomers: o-xylene, m-xylene, and p-xylene. Long-term exposure to low doses of xylene in the environment has been linked to a higher risk of lung cancer. However, the molecular mechanisms behind this link are still not fully understood. In this study, we used a combination of network toxicology and molecular docking to investigate how xylene may contribute to the development of non-small cell lung cancer (NSCLC). We first identified 115 potential target genes related to xylene exposure by searching several public databases, including CHEMBL, STITCH, GeneCards, and OMIM. Further screening using the STRING platform and Cytoscape analysis highlighted five core targets: IL1A, H3C13, ITGAM, CCR5, and COMT. We utilized scRNA-seq data to analyze the expression patterns of core targets across distinct cell subpopulations, the majority of core targets were expressed in immune cells. We then performed GO and KEGG pathway enrichment analysis. These results showed that the five target genes are mainly involved in cancer-related pathways, such as ECM-receptor interaction, focal adhesion, chemical carcinogenesis, and the PI3K-Akt signaling pathway. Molecular docking results confirmed that xylene isomers have strong binding affinities with the proteins encoded by these genes. This suggests that xylene may disrupt important cellular signals and promote tumor growth. In conclusion, our study provides new insight into how xylene might cause NSCLC at the molecular level. It also shows the usefulness of network toxicology in evaluating health risks from environmental chemicals. These findings may help guide future efforts in prevention and treatment strategies.

The aim of the present study was to investigate the effects of SIVA‑1 silencing on the drug resistance and biological functions of cisplatin (DDP)‑resistant human gastric cancer cells (AGS/DDP), and to explore the mechanism underlying its occurrence. AGS/DDP cells with stable silencing of SIVA‑1 were established by molecular biology techniques. The Cell Counting Kit‑8 assay was used to investigate the effect of SIVA‑1 silencing on drug sensitivity in AGS/DDP cells by measuring the IC50 of Adriamycin, DDP and vincristine. The findings demonstrated that the suppression of SIVA‑1 in AGS/DDP cells markedly augmented the resistance to DDP. In addition, cell proliferation, cell migration, cell invasion and cell apoptosis were assessed using colony formation, cell scratch, Transwell and cell apoptosis assays, respectively. The results of these assays demonstrated that silencing SIVA‑1 notably increased the proliferation, migration and invasion of AGS/DDP cells, while concurrently inhibiting their apoptosis. Furthermore, the effects of SIVA‑1 silencing on drug‑resistant gastric cancer cells in vivo were confirmed using a subcutaneous xenograft model in nude mice. The results demonstrated that silencing SIVA‑1 led to a notable increase in tumor volume, growth rate and weight. The bioinformatics analyses results indicated that SIVA‑1 may have an interactive relationship with Bcl‑2, BAX, X‑linked inhibitor of apoptosis protein (XIAP), MAPK8 and baculoviral inhibitor of apoptosis repeat‑containing 5 (BIRC5), and could participate in the mitochondria‑dependent apoptosis pathway. The results of reverse transcription‑quantitative PCR and western blotting indicated that silencing SIVA‑1 in AGS/DDP cells promoted the expression levels of Bcl‑2, XIAP, MAPK8 and BIRC5, and inhibited the expression levels of BAX. In conclusion, silencing SIVA‑1 has been shown to modify sensitivity to DDP and biological function in drug‑resistant gastric cancer cells, either directly or indirectly. This phenomenon may be associated with the Bcl‑2/BAX‑mediated, mitochondria‑dependent apoptosis pathway.

Colorectal cancer (CRC) remains one of the leading causes of cancer‑related mortality worldwide. Despite advances in targeted therapies, drug resistance and limited efficacy in KRAS‑mutant CRC continue to present clinical challenges. Antrodia cinnamomea, a medicinal fungus, demonstrates antitumor properties; however, the mechanisms of its triterpenoid compound, 4‑acetylantrocamol LT3 (LT4), remain unclear. The present study investigated the effects of LT4 on KRAS‑mutant HCT116 CRC cells using cell viability, colony formation and migration assays. Western blotting was also employed to examine key signaling pathways. Transcriptome profiling via RNA sequencing was followed by Kyoto Encyclopedia of Genes and Genomes/Gene Ontology enrichment and protein‑protein interaction network analyses using STRING, CytoHubba and Molecular Complex Detection (MCODE). Molecular docking with PI3Kγ (PDB: 1E7U) was conducted to evaluate the predicted binding position and docking energy of LT4. The results indicated that LT4 significantly inhibited HCT116 cell proliferation and migration, induced a mesenchymal‑to‑epithelial transition, suppressed PI3K/AKT/mTOR and ERK signaling and activated the GSK3β/FOXO and phosphorylated‑p38/p21 axes. LT4 also reduced the levels of cyclooxygenase‑2 and anti‑apoptotic proteins (Bcl‑2 and Bcl‑XL) and reduced the expression of the mitochondrial respiratory chain protein cytochrome c oxidase subunit IV. Transcriptomic analysis identified the PI3K/AKT pathway as the most significantly enriched signaling cascade. Network topology analyses highlighted solute carrier family 3 member 2, Cyclin D1, phosphoserine aminotransferase 1 and ChaC glutathione‑specific γ‑glutamylcyclotransferase 1 as central nodes, linking the effects of LT4 to nutrient signaling, redox homeostasis and serine metabolism. Molecular docking confirmed that LT4 stably occupied the ATP‑binding pocket of PI3Kγ with a binding energy comparable to wortmannin and a conformation similar to antroquinonol. In conclusion, to the best of our knowledge, the present study is the first to comprehensively demonstrate the multi‑target anti‑CRC effects of LT4, highlighting its potential as a therapeutic agent, especially in KRAS‑mutant CRC.

MAGE family member A1 (MAGEA1), a cancer‑testis antigen (CTA), is aberrantly expressed in several malignancies such as lung and liver cancers. However, its role in cervical cancer remains to be elucidated. The present study investigated the functional significance and therapeutic potential of MAGEA1 in cervical cancer using lentiviral short hairpin RNA‑mediated knockdown, a series of functional assays, RNA sequencing (RNA‑seq), and nude mouse xenograft models. It was found that MAGEA1 was upregulated in cervical cancer cells and its knockdown substantially suppressed cell proliferation, migration, invasion, and in vivo tumor growth. RNA‑seq analysis further revealed that MAGEA1 silencing altered pathways related to apoptosis, DNA repair, and metabolism. Moreover, MAGEA1 knockdown enhanced chemosensitivity, indicating a potential role in mediating drug resistance. Collectively, the findings identified MAGEA1 as a key oncogenic driver in cervical cancer and highlighted its promise as both a prognostic biomarker and a therapeutic target, offering novel avenues for personalized treatment strategies in cervical cancer.

The myeloid oncogene TRIB2 is a key driver of acute myeloid leukaemia (AML) pathogenesis, promoting chemoresistance and blocking differentiation through ubiquitin-mediated degradation of the C/EBPα transcription factor. Despite its stable and sometimes elevated expression across AML subtypes, TRIB2 remains a clinically untargeted vulnerability. Here, we present a comprehensive investigation into TRIB2 degradation mechanisms using multimodal approaches, including CRISPR knockout, mutational protein stability, small molecule TRIB2 engagement, and evaluation of a novel targeted protein degrader (TRIB2-PROTAC). We identify afatinib, a multi-ERBB covalent inhibitor, as a rapid inducer of TRIB2 degradation, triggering AML cell death potentially via signalling pathways distinct from ERBB. Importantly, TRIB2 degradation synergised with cytarabine, the frontline AML chemotherapy, amplifying therapeutic efficacy. Mapping of TRIB2 ubiquitination sites revealed Lys-63 as critical for its own proteolytic turnover, and a Lys-to-Arg degradation-resistant mutant (KallR) conferred enhanced chemoresistance and increased leukaemic engraftment in vivo. CRISPR-mediated TRIB2 knockout validated an essential role in AML cell survival. Consistently, the novel TRIB2-PROTAC (compound 5K) achieved robust TRIB2 degradation and AML cell killing at low micromolar concentrations. These findings establish TRIB2 as a compelling therapeutic target in AML and demonstrate that leveraging the ubiquitin-proteasome system to degrade TRIB2 offers a promising strategy to overcome chemoresistance. The present work provides strong preclinical rationale for the development of TRIB2-targeting therapies in AML.