Current Issues in Molecular Biology最新文献

{"title":"Reactive Sulfur Species and Protein Persulfidation: An Emerging Redox Axis in Human Health and Disease.","authors":"Celia María Curieses Andrés, Fernando Lobo, José Manuel Pérez de la Lastra, Elena Bustamante Munguira, Celia Andrés Juan, Eduardo Pérez Lebeña","doi":"10.3390/cimb47090765","DOIUrl":"10.3390/cimb47090765","url":null,"abstract":"<p><p>Reactive sulfur species (RSS)-hydrogen sulfide (H₂S), low-molecular-weight persulfides/polysulfides and protein persulfidation-constitute a third redox axis alongside ROS and RNS. Nanomolar H₂S, produced by trans-sulfuration (CBS/CSE) and 3-MST, is oxidized by sulfide-quinone reductase to persulfides that fuel the respiratory chain while curbing superoxide. Reversible persulfidation reprograms cysteine sensors in metabolism (GAPDH), inflammation (NLRP3, p47^phox) and transcription (Keap1/NRF2), linking RSS to energy balance, vasodilation, innate immunity and neuroplasticity. Disrupted sulfur signaling-deficit or overload-contributes to heart failure, sarcopenia, neurodegeneration, cancer and post-COVID syndromes. Therapeutically, slow-release donors (SG1002, GYY4137), mitochondria-targeted vectors (AP39), photo- or thiol-activated \"smart\" scaffolds, diet-derived polysulfides/isothiocyanates and microbiota engineering aim to restore the protective RSS window. Key challenges are a narrow therapeutic margin and real-time quantification of persulfide fluxes. Harnessing RSS therefore offers a route to rebalance redox homeostasis across diverse chronic diseases.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IDO Activation Affects BDNF/TrkB Signaling Pathway, Oxidative Stress, and Mitochondrial Enzymatic Activities in Temporal Lobe Epilepsy.","authors":"Jingwen Xu, Liping Wei, Junling Fu, Ziting Kong, Lun Cai","doi":"10.3390/cimb47090764","DOIUrl":"10.3390/cimb47090764","url":null,"abstract":"<p><p>Indoleamine 2,3-dioxygenase (IDO) activation by seizures elevates toxic tryptophan metabolites linked to seizure exacerbation. Brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling, oxidative stress, and mitochondrial respiratory chain complex dysfunction contribute to temporal lobe epilepsy (TLE), but their regulatory links remain unclear. Male Kunming mice were grouped into Control, Control + 1-Methyl-DL-tryptophan (1-MT), TLE, and TLE + 1-MT. TLE was induced with 300 mg/kg pilocarpine. Two weeks after modeling, 1-MT (50 mg/kg) was administered twice daily for two weeks in 1-MT groups. Assessments included video monitoring to record seizure frequency and duration; Nissl and Fluoro-Jade B (FJB) staining to evaluate neuronal damage; real-time quantitative PCR (qRT-PCR) and Western blot to detect IDO, BDNF, and TrkB expression; assays for the following oxidative stress markers: malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT); and detection of mitochondrial complex I/IV activities. Results showed TLE mice had significantly increased IDO expression, BDNF/TrkB over-activation, elevated oxidative stress, impaired mitochondrial complex I/IV activities, severe neuronal damage, and increased seizure frequency/duration. 1-MT intervention reversed all these pathological changes, restoring levels to near-control status. This indicates IDO activation promotes TLE progression, which is associated with modulation of the BDNF/TrkB signaling pathway, exacerbation of oxidative stress, and impairment of mitochondrial complex I/IV activities-supporting IDO as a potential therapeutic target for TLE.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Therapeutic Strategies for HPV-Related Cancers: From Gene Editing to Precision Oncology.","authors":"Muharrem Okan Cakir, Guldide Kayhan, Betul Yilmaz, Mustafa Ozdogan, G Hossein Ashrafi","doi":"10.3390/cimb47090759","DOIUrl":"10.3390/cimb47090759","url":null,"abstract":"<p><p>Human papillomavirus (HPV) is a major etiological factor in cervical, anal, and oropharyngeal cancers. Although prophylactic vaccines have substantially reduced infection rates, effective therapeutic options for established HPV-associated malignancies remain limited. This review provides an up-to-date overview of emerging strategies to treat HPV-driven tumours. Key approaches include immune checkpoint inhibitors, therapeutic vaccines such as VGX-3100 and PRGN-2012, and gene-editing tools like CRISPR/Cas9. Epigenetic drugs, particularly histone deacetylase inhibitors, show promise in reactivating silenced tumour suppressor genes and enhancing antitumour immunity. In addition, natural bioactive compounds and plant-derived molecules are being explored as complementary anti-HPV agents, while drug repurposing and combination therapies offer cost-effective opportunities to broaden treatment options. We also highlight the role of patient-derived organoid models as powerful platforms for personalized drug screening and functional assessment. By integrating these therapeutic innovations with precision oncology approaches, this review outlines a multidimensional framework aimed at improving clinical outcomes and quality of life for patients with HPV-associated cancers.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12469042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Field-Deployable Detection of Chestnut Blight Pathogen <i>Cryphonectria parasitica</i> Using Enzyme-Mediated Duplex Exponential Amplification.","authors":"Shuai Wang, Zhongwei Feng, Yiming Liu, Changyun Tang, Kai Guo, Jiafu Hu","doi":"10.3390/cimb47090762","DOIUrl":"10.3390/cimb47090762","url":null,"abstract":"<p><p>Chestnut blight caused by <i>Cryphonectria parasitica</i> poses a major threat to chestnut plantations worldwide. Rapid, field-deployable diagnostic tools are essential for effective disease surveillance and management. Here, we developed and validated an enzyme-mediated duplex exponential amplification (EmDEA) assay for the specific and sensitive detection of <i>C. parasitica</i>. The assay successfully distinguished <i>C. parasitica</i> from non-target fungal species with a detection limit of 10 pg of genomic DNA per reaction. Application to naturally infected bark samples yielded results consistent with those of conventional qPCR. The complete workflow, including crude DNA extraction and fluorescence-based detection under isothermal conditions, was completed within 35 min. Our findings demonstrate that the EmDEA assay is a sensitive, robust, and field-adaptable tool that can be used for the early detection of chestnut blight, with significant potential for deployment in resource-limited environments.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Diverse Roles of Mitochondria in Regulating Cancer Metastasis.","authors":"Shiyu Tang, Biao Yang","doi":"10.3390/cimb47090760","DOIUrl":"10.3390/cimb47090760","url":null,"abstract":"<p><p>Metastasis is the primary cause of cancer-related deaths. As a multi-step process, tumor metastasis encompasses several key aspects. Tumor cells first traverse the basement membrane and subsequently invade the surrounding vascular or lymphatic systems, ultimately leading to secondary colonization. Throughout the progression of metastasis, tumor cells can overcome selective pressures and transition between different cellular states, depending on the diverse functions of mitochondria. Mitochondria not only function as energy generators but also co-evolve with host cells, acting as critical signaling hubs in various biological pathways. Under sustained stress conditions such as nutrient deficiency, cellular stress, and the reprogramming of gene expression, alterations in mitochondrial morphology and function can prevent cell death and facilitate the targeted transformation of oncogenes, tumor progression, and the emergence of invasive cell phenotypes. The multifaceted roles of mitochondria enable tumor cells to evade unfavorable environments and establish colonies in more conducive sites. In summary, this review consolidates the complex interactions between mitochondria and cancer while elucidating their significant role in cancer metastasis and therapeutic responses.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Molecular Profiling and Bioactivity Analysis of Algerian Propolis: Antioxidant, Antibacterial Activities, and In Silico NRF2-KEAP1 Pathway Modulation.","authors":"Amel Reguig, Ahmed Messai, Ibtissam Kahina Bedaida, Diana C G A Pinto, Chawki Bensouici, Abdelmoneim Tarek Ouamane, Artur M S Silva, Jean-Philippe Roy","doi":"10.3390/cimb47090761","DOIUrl":"10.3390/cimb47090761","url":null,"abstract":"<p><p>Propolis, a natural bee-derived product rich in diverse phytochemicals with potential therapeutic benefits, remains underexplored in Algeria. This study investigated the molecular profile, antioxidant capacity, and antibacterial activity of propolis sourced from two bioclimatically distinct Algerian regions (humid subtropical Batna and hot desert Biskra) using electrospray ionization mass spectrometry, ultra-high-performance liquid chromatography with diode array detection, and gas chromatography-mass spectrometry. Significant regional variations were observed, with propolis extract 2 (PE2) exhibiting a higher bioactive content, including a constituent not previously reported in propolis. Antioxidant assays (2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), ferric reducing antioxidant power, and phenanthroline) demonstrated that PE2 consistently outperformed propolis extract 1 and the reference standards (DPPH IC₅₀: 27.74 µg/mL; FRAP: 5.16 µg/mL). Antibacterial testing demonstrated potent bactericidal effects, particularly for PE2, with minimum inhibitory concentration values equivalent to the minimum bactericidal concentrations required against <i>Staphylococcus aureus</i> ATCC 25923 (18.75 µg/mL) and <i>Escherichia coli</i> ATCC 25922 (133 µg/mL). Molecular docking identified nine bioactive compounds with high KEAP1 binding affinity, with 1,3-<i>O</i>-caffeoyl-dihydrocaffeoylglycerol (first time reported in propolis) showing the strongest binding affinity (-11.02 Kcal/mol). In silico pharmacokinetic predictions further verified its drug-like properties. These findings suggest the tested Algerian propolis samples, as a source of natural alternative antioxidants and antimicrobials, provide a basis for future research in drug discovery and development.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering the Tumorigenic Blueprint of PFOS and PFOA Through Multi-Organ Transcriptomic Analysis of Biomarkers, Mechanisms, and Therapeutic Targets.","authors":"Krisha Mathur, Aleezah Khaliq, Stephanie Park, Nathan Chu, Vaishnavi M Burra, Norah Kanukolanu, Ellen Costello, Sivanesan Dakshanamurthy","doi":"10.3390/cimb47090763","DOIUrl":"10.3390/cimb47090763","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFASs), called forever chemicals, persist in the environment and bioaccumulate, posing significant health risks. While epidemiological studies have linked exposure to specific PFAS types, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), to an increased incidence of various cancers, specific tumorigenesis mechanisms are unknown. Here, we investigated the potential molecular markers and signatures of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) tumorigenesis. We performed a comprehensive transcriptomic analysis across multiple species and tissue types (<i>N</i> = 529) using PFOS and PFOA-exposed RNA-Seq samples. Conserved signatures demonstrate significant disruptions in seven key carcinogenic characteristics including metabolic reprogramming, epigenetic modifications, immune suppression, oxidative stress, and genomic instability. Tumorigenic markers such as <i>SERPINE1</i>, <i>FN1</i>, <i>PLIN2</i>, <i>ALDOA</i>, <i>TRIB3</i>, and <i>TSC22D3</i> and their associated pathways may act independently or synergistically to promote a pro-tumorigenic environment. Additionally, PPARα, LARP1, ACOX1, MYC, and MYCN were identified as key upstream regulators supporting disruptions in lipid metabolism, oxidative stress, and uncontrolled cell proliferation. In liver samples, low concentrations of PFOS and PFOA were sufficient to exhibit tumorigenic signatures associated with tumorigenesis initiation and development. Inferred mechanisms of ccRCC initiation and development were linked to lipid metabolism dysregulation and immunosuppressive signaling. In prostate and testicular xenograft tumor models, carcinogenic mechanisms for tumor progression and promotion were hypothesized. Receptor-mediated signaling and protein synthesis was disrupted in prostate cancer and epigenetic alterations and ECM remodeling observed in testicular cancer. We also explored potential therapeutic rescue strategies, including chemopreventive agents for early intervention. All our findings provide hypotheses for PFOS/PFOA-induced tumorigenesis; however, experimental studies are required to establish translational relevance. All the R codes developed in this study are publicly available.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracellular Mis-Localization of Modified RNA Molecules and Non-Coding RNAs: Facts from Hematologic Malignancies.","authors":"Argiris Symeonidis, Argyri Chroni, Irene Dereki, Dionysios Chartoumpekis, Argyro Sgourou","doi":"10.3390/cimb47090758","DOIUrl":"10.3390/cimb47090758","url":null,"abstract":"<p><p>The intracellular topography of RNA molecules, encompassing ribonucleotides with biochemical modifications, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), adenosine to inosine (A → I) editing, and isomerization of uridine to pseudouridine (Ψ), as well as of non-coding RNA molecules, is currently studied within the frame of the epigenome. Circulating RNA molecules in the intracellular space that have incorporated information by carrying specific modifications depend on the balanced activity and correct subcellular installation of their modifying enzymes, the \"writers\", \"readers\" and \"erasers\". Modifications are critical for RNA translocation from the nucleus to the cytoplasm, for stability and translation efficiency, and for other, still-uncovered functions. Moreover, trafficking of non-coding RNA molecules depends on membrane transporters capable of recognizing signal sequences and RNA recognition-binding proteins that can facilitate their transport to different intracellular locations, guiding the establishment of interconnection possibilities with different macromolecular networks. The potential of long non-coding RNAs to form multilayer molecular connections, as well as the differential topology of micro-RNAs in cell nuclei, compared to cytoplasm, has been recognized by several studies. The study of the intercellular compartmentalization of these molecules has recently become feasible thanks to technological progress; however, a wealth of information has not yet been produced that would lead to safe conclusions regarding non-coding RNA's contributions to the early steps of pathogenesis and disease progression in hematological malignancies. Both, the bone marrow, as the main hematopoietic tissue, and the lymphoid tissues are composed of cells with highly reactive potential to signals affecting the epigenome and initiating cascade pathways in response. Independently or in combination with coexistent driver genetic mutations, especially mutations of enzymes involved in epigenomic surveillance, intracellular microenvironmental alterations within the cell nuclear, cytoplasmic, and mitochondrial compartments can lead to disorganization of hematopoietic stem cells' epigenomes, promoting the generation of hematological malignancies. In this review, we discuss the various intracellular processes that, when disrupted, may result in the ectopic placement of RNA molecules, either inducing specific modifications or non-coding molecules or promoting hematological malignant phenotypes. The crosstalk between mitochondrial and nuclear genomes and the complex regulatory effects of mis-localized RNA molecules are highlighted. This research approach may constitute a field for new, more specifically targeted therapies in hematology based on RNA technology.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Let-7c/RUNX1 Axis Promotes Cervical Cancer: A Bioinformatic Analysis.","authors":"Ana Elvira Zacapala-Gómez, Gabriela Hernández-Galicia, Francisco Israel Torres-Rojas, Christian Johana Baños-Hernández, Julio Ortiz-Ortiz, Hilda Jiménez-Wences, Gabriela Elizabeth Campos-Viguri, Verónica Antonio-Véjar, Judit Alarcón-Millán, Eric Genaro Salmerón-Bárcenas","doi":"10.3390/cimb47090757","DOIUrl":"10.3390/cimb47090757","url":null,"abstract":"<p><strong>Background: </strong>Cervical cancer (CC) ranks as the third most common cancer in incidence and mortality in females worldwide. Let-7c is a tumor suppressor miRNA, and its role has been little studied in CC. Runt-related transcription factor 1 (RUNX1) is upregulated in several human cancers, such as colorectal cancer. It is a transcription factor that promotes cell proliferation, metastasis, chemotherapy resistance and angiogenesis in colorectal cancer. In this study, we performed a bioinformatic analysis to understand how Let-7c and RUNX1 are involved in the development of CC.</p><p><strong>Methods: </strong>We performed a bioinformatic analysis of Let-7c in CC using GSE and TCGA datasets from GEO, KM-plotter, miRPathDB and Enrich databases. Then, we conducted a comprehensive analysis of RUNX1's role in CC using TCGA, GSE and HPA datasets from OncoDB, CISTROME, ExPASy, Alibaba, ALGGEN, ENCODE, IGV, GEO, KM-plotter and DiseaseMeth databases.</p><p><strong>Results: </strong>We found that Let-7c expression is decreased in CC. Interestingly, we identified a transcription factor known as RUNX1, as a potential target of Let-7c. Finally, we suggest that RUNX1 could regulate the expression of several genes, promoting CC.</p><p><strong>Conclusions: </strong>The Let-7c/RUNX1 axis promotes CC.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interpretable Transfer Learning for Cancer Drug Resistance: Candidate Target Identification.","authors":"Wenjie Zhang, Xisong Wu, Liang Chen, Xinyue Wan","doi":"10.3390/cimb47090753","DOIUrl":"10.3390/cimb47090753","url":null,"abstract":"<p><p>Tumor drug resistance exhibits substantial heterogeneity across cancer types, reflecting distinct molecular mechanisms in each malignancy. To characterize this complexity, we developed a pan-cancer transfer learning framework that integrates bulk RNA-seq data with a residual variational autoencoder (Res VAE) backbone. Five models were trained on the Genomics of Drug Sensitivity in Cancer (GDSC) dataset, which includes drug response profiles for 72 chemotherapeutic agents. Among them, three models are specially designed by incorporating variational autoencoders and large pretrained models (LLMs): the LLM large VAE (VAE_LL), the LLM small VAE (VAE_LS), and the LLM distillation VAE (VAE_LD). Random Forest (RF) and eXtreme Gradient Boosting (XGB) were included as ensemble learning baselines. After internal cross-validation, the top four models (VAE_LL, VAE_LD, XGB, and RF) were applied to five representative TCGA cohorts comprising 1,836 patients. For each cancer type, resistance to nine clinically relevant first-line drugs was modeled, resulting in 180 drug-cancer prediction tasks. Among all models, VAE_LD achieved the best overall performance, with a mean AUC of 0.81 and an F1 score of 0.92 on the GDSC benchmark, and maintained strong predictive power in the clinical validation phase. Interpretation analyses identified tumor-specific resistance biomarkers with clinical significance. In lung adenocarcinoma, elevated expression of <i>TFF1</i> was repeatedly associated with resistance to Gefitinib and correlated with poor patient prognosis, indicating its potential as a therapeutic target. In glioblastoma, <i>OPALIN</i>, <i>LTF</i>, <i>IL2RA</i>, and <i>SLC17A7</i> were implicated in Temozolomide resistance through pathways related to epithelial differentiation and angiogenesis. In conclusion, the VAE_LD model offers a high-performing and interpretable approach for predicting drug resistance across multiple tumor types. It supports the identification of clinically actionable biomarkers and provides a robust framework for precision oncology applications.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"47 9","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}