Search Results (8,648)

Fungal endophytes are symbiotic microorganisms that establish strong relationships inside plant tissues, providing potential advantages, especially in grasses, by enhancing tolerance to both abiotic and biotic stresses. This review investigates the molecular mechanisms through which fungal endophytes mediate stress tolerance, targeting host–pathogen interactions. By modulating pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and effector proteins, fungal endophytes may contribute to priming the plant’s immune system, enhancing its resistance to pathogen invasion. Moreover, endophyte colonization regulates core processes such as osmotic regulation, reactive oxygen species (ROS) detoxification, and secondary metabolite biosynthesis that enable plants to tolerate environmental stresses like drought, heat, and salinity. The review highlights the impact of endophytes on immune priming, systemic acquired resistance (SAR), and the regulation of non-coding RNAs that regulate host gene networks associated with stress tolerance. Furthermore, the integration of advanced multi-omics techniques genomics, transcriptomics, proteomics, metabolomics, and fluxomics has revealed emerging insights into the genetic and metabolic pathways driving these symbiotic associations. However, grass-specific molecular datasets remain limited, and the consistency of endophyte-mediated tolerance across host species and environmental conditions is not yet fully resolved. Fungal endophytes increase grass stress resilience through coordinated pathogen recognition, RNA regulation, and metabolic reprogramming while AI-assisted multi-omics approaches are emerging as tools for identifying candidate regulatory networks, although empirical validation in grass–endophyte systems remains limited. Together, these advances highlight the potential for climate-smart and sustainable crop improvement. Future research integrating functional genomics, field validation, and biosafety assessment will be essential for translating endophyte-based strategies into reliable agricultural applications. Full article

Plants in agricultural systems rarely face single stressors; instead, they encounter concurrent biotic (pathogen, pests) and abiotic (drought, salinity, heavy metals) stresses that causes severely reduce crop yields and endanger food security. The traditional methods of breeding, genetic engineering, and agrochemicals tend to target individual stresses and still do not suffice in the complex field conditions. Compared to these approaches, nanotechnology offers distinct advantages: nanoparticles (NPs) can be applied as foliar sprays or seed treatments without lengthy breeding cycles or regulatory hurdles associated with genetically modified organisms. However, nanotechnology is not inherently “better” but rather complementary to crop engineering; each approach has specific strengths. Breeding and genetic engineering provide heritable, long-term solutions, while nanotechnology offers immediate, season-specific, and reversible interventions. Cross-tolerance, the phenomenon whereby exposure to one stress enhances tolerance to another, offers a promising alternative. This review critically examines how NPs act as stress-priming agents that induce cross-tolerance by activating overlapping defense networks, including antioxidant systems (SOD, CAT, APX), phytohormonal crosstalk (ABA, SA, JA), osmolyte homeostasis, and stress-responsive gene expression. We synthesize current evidence on NP uptake, translocation, and cellular interactions, and evaluate their dual role in directly suppressing pathogens while simultaneously enhancing plant immune responses and physiological resilience. However, efficacy is highly dose-dependent: low, subtoxic doses prime defense through hermetic ROS signaling, whereas supraoptimal doses cause phytotoxicity. The current challenges in nano-mediated stress alleviation include: (i) a persistent laboratory-to-field translation gap, with field outcomes averaging only 60–70% of greenhouse efficacy; (ii) dose-dependent phytotoxicity; (iii) poor reproducibility across studies; (iv) scalability and formulation stability issues; and (v) insufficient understanding of long-term environmental fate, including soil accumulation, non-target organism effects, and food chain safety. Future research should consider field-validated formulations (e.g., SiNPs, ZnONPs, Fe₃O₄NPs) across major staple crops); integrating nanotechnology with precision agriculture through nanosensors, remote sensing, and artificial intelligence for site-specific, dose-optimized applications;developing smart, biodegradable nanoparticles with stimuli-responsive release; and establishing harmonized regulatory frameworks for nano-agrochemical approval. When deployed responsibly, nanoparticle-induced cross-tolerance represents a sustainable approach to improve crop resistance against multifactorial stress, with significant implications for climate-resilient agriculture and global food security. Full article

The rise in antimicrobial resistance represents a significant challenge to global health. The reason partially lies in an inappropriate use of conventional antibiotics and the subsequent rapid spread of multidrug-resistant pathogen strains. This emergency requires an urgent search for conceptually new antimicrobial agents. A viable alternative to conventional antibiotics is antimicrobial peptides (AMPs), which are ribosomally synthesized molecules with considerable potential as next-generation anti-infectious therapeutics. Previously, we have reported on the β-hairpin peptide Ap9, an analog of abarenicin from the marine polychaeta Abarenicola pacifica, with potent activity against key Gram-negative pathogens. Here, it is shown that Ap9 acts in a manner resembling polymyxin B, namely via interaction with lipopolysaccharide (LPS), and retains its activity against polymyxin-resistant isolates without observed cross-resistance, and causes insignificant damage in cytoplasmic membrane at bactericidal concentrations. NMR spectroscopy reveals that LPS binding induces a conformational rearrangement of Ap9, its dimer formation, and local structural remodeling of the peptide region (residues 8–12) into 3₁₀-helix. Bacterial resistance to Ap9 was found to be relatively low with a reduced susceptibility associated with infrequent genetic alterations, such as the mutation in lptD or the deletion in mlaA. Furthermore, Ap9 demonstrates a favorable tolerability, a wider therapeutic window than that of polymyxin B, and a sufficiently long half-life through the systemic use, as well as in vivo efficacy in murine models of Gram-negative infections, including sepsis caused by the mcr-1-harboring Escherichia coli strain. The obtained results point to Ap9 as a promising candidate for further preclinical studies aimed at development of an alternative to polymyxins. Full article

This study compared intestinal polyamine metabolism and barrier function between Ningxiang (NX) and Duroc × Landrace × Yorkshire (DLY) piglets under baseline conditions and following ETEC challenge. Experiment 1 (baseline, n = 12/breed) assessed colonic barrier integrity, immune status, polyamines, and microbiota. Experiment 2 (ETEC challenge, n = 8/group/breed) evaluated responses to oral ETEC (10⁹ CFU) over 3 days. Under baseline conditions, NX piglets showed superior barrier integrity, higher goblet cell numbers and mucin 2 (MUC2) protein expression, and lower plasma levels of intestinal permeability markers—diamine oxidase (DAO), D-lactate (DLA), and endotoxin (ET)—compared with DLY piglets. NX piglets also exhibited reduced colonic pro-inflammatory cytokine levels (IL-6 and IL-1β) and higher expression of immune-related markers (CD3, CD68, and IgA) versus DLY piglets. In contrast, DLY piglets displayed more active microbial polyamine metabolism in the colon, with higher concentrations of putrescine, spermidine, and spermine, as well as increased ornithine decarboxylase (ODC) expression. 16S rRNA sequencing revealed greater microbial diversity and enrichment of taxa (Muribaculaceae_unclassified, Prevotella) in NX piglets, whereas DLY piglets showed enrichment of polyamine-associated genera (Collinsella, Veillonella). Following the ETEC challenge, DLY piglets displayed pronounced polyamine upregulation, including elevated polyamine levels and ODC1 expression. Conversely, NX piglets maintained more stable polyamine metabolism, higher expression of tight junction proteins (ZO-1 and occludin), lower plasma permeability markers, reduced pro-inflammatory cytokine expression (IL-6, IL-1β, IL-22), and increased anti-inflammatory IL-10 expression. Collectively, these findings demonstrate that NX piglets possess superior intestinal barrier integrity and immune maturity, while DLY piglets exhibit a more active but stress-responsive polyamine metabolic phenotype. The divergent metabolic and immune responses to ETEC challenge underscore the distinct strategies employed by these two breeds in maintaining gut homeostasis. These findings provide preliminary insights that may inform future breeding strategies aimed at enhancing intestinal health and disease resistance in pigs, pending validation in broader genetic backgrounds and mechanistic studies. Full article

Background/Objectives: The rapid emergence of antimicrobial resistance (AMR) is driven not only by antibiotic selective pressure but also by bacterial adaptive responses that enhance genetic diversification under stress. The SOS response, regulated by the RecA-LexA axis, plays a central role in coordinating DNA repair, mutagenesis, and phenotypic adaptation. Targeting this pathway represents a promising strategy to limit bacterial adaptability without directly affecting viability. This study aimed to evaluate benzoxaborole-based compounds as potential inhibitors of the LexA regulatory pathway. Methods: A drug repurposing approach was employed to investigate the benzoxaborole scaffold and the clinically approved derivatives tavaborole and crisaborole. Biochemical assays were used to assess LexA autocleavage in a RecA-dependent co-protease system. Molecular docking analyses were performed to evaluate compound binding within the LexA catalytic site. Microbiological assays were conducted to examine the effects on antibiotic-induced filamentation and biofilm formation under different growth conditions. Results: Selected benzoxaboroles inhibited LexA autocleavage, with tavaborole showing the strongest inhibitory profile in the biochemical assay. Docking analyses supported these findings, indicating stable binding within the LexA catalytic site near the catalytic serine residue. At the cellular level, tavaborole and benzoxaborole significantly reduced levofloxacin-induced filamentation at sub-inhibitory concentrations. Both compounds also decreased biofilm formation under nutrient-limited conditions, while no significant effects were observed on preformed biofilms. Crisaborole showed limited cellular activity despite measurable biochemical effects. Conclusions: These findings identify benzoxaboroles as modulators of the LexA-dependent SOS response and support the potential repurposing of clinically approved compounds as adjuvants to limit bacterial adaptive responses associated with antimicrobial resistance. Full article

Background: Cymbidium kanran ‘Zhushalan’ is a famous traditional Chinese orchid with high ornamental and economic value. As its market expands, there is a need to improve its key horticultural traits and stress resistance. Unfortunately, these traits are difficult to breed using traditional methods, and an optimal regeneration and genetic transformation system for C. kanran has yet to be established. Methods: This study evaluated the factors affecting Agrobacterium-mediated genetic transformation and regeneration of C. kanran ‘Zhushalan’ using rhizomes obtained from seedlings as receptor material. Results: The highest regeneration frequency was achieved after pre-cultivating the rhizomes in the dark on ½ MS medium for 10 days. The genetic transformation system was optimized as follows: Agrobacterium strain, EHA105; optimal concentration of Agrobacterium solution, OD₆₀₀ = 0.6; 100 mg·L⁻¹ acetosyringone; an infection time of no more than 40 min; and co-culturing for one to three days. Positive strains were screened using meropenem (15 mg·L⁻¹) and hygromycin (50 mg·L⁻¹) and confirmed through PCR and qRT-PCR. A transformation rate of 11.67% was achieved. Conclusions: An efficient regeneration and genetic transformation system for C. kanran ‘Zhushalan’ has been established for developing transgenic technologies. Our findings will stimulate research on functional genes and molecular breeding related to C. kanran. Full article

Staphylococcus pseudintermedius is an opportunistic bacterium previously associated with dogs but has recently been found in human infections, raising zoonotic concerns. Genomic characterization of human S. pseudintermedius isolates can provide preliminary information on antibiotic resistance, pathogenicity, and genomic features relevant to host range. Two S. pseudintermedius isolates (hereafter referred to as S. pseudintermedius EGH1 and S. pseudintermedius EGH2) from human clinical samples in Egypt were sequenced using the Illumina NovaSeq X Plus platform. To assess genetic relatedness to human S. pseudintermedius isolates worldwide, multilocus sequence typing (MLST), pangenome analysis, and antimicrobial resistance gene profiling were performed. The sequencing produced a total of 9,499,989 reads for S. pseudintermedius EGH1 and 9,567,531 reads for S. pseudintermedius EGH2. Sequences were assembled with Geneious Prime^® 2025 and annotated using NCBI Prokaryotic Genome Annotation Pipeline v6.10. Pangenome analysis identified 9574 genes, comprising 1681 core genes (17.56%), 180 soft-core genes (1.88%), 837 shell genes (8.74%), and 6876 cloud genes (71.82%). MLST was conducted on human S. pseudintermedius genome assemblies using MLST v2.23.0. The analysis revealed both isolates as novel sequence types: S. pseudintermedius EGH1 was assigned ST-3037 with a new allele (purA-107), and S. pseudintermedius EGH2 was assigned ST-2874. Clonal relationships among S. pseudintermedius isolates were evaluated using the eBURST algorithm. This study presents the first next-generation genome sequencing and comparative genomic analysis of S. pseudintermedius isolates from humans in Egypt. Future studies integrating genomic, epidemiological, and phenotypic data are required. Full article

Antimicrobial resistance in Escherichia coli (E. coli) is a major public health concern globally, driven by increased resistance to commonly used antimicrobial agents such as β-lactams and fluoroquinolones. The main goal of our research is to develop a machine learning framework to predict antimicrobial resistance in E. coli by integrating antimicrobial susceptibility testing data with genomic biomarker analysis. A dataset comprising 17,122 E. coli clinical isolates was obtained from the Bacterial and Viral Bioinformatics Resource Center (BV-BRC). After preprocessing, fivefold cross-validation was used to train and test five machine learning models: Random Forest, XGBoost, Support Vector Machine, Logistic Regression, and k-Nearest Neighbors. The highest-performing model was XGBoost, with 0.86 accuracy and 0.932 ROC-AUC, followed by Random Forest, with 0.82 accuracy and 0.89 ROC-AUC. Phylogenetic analysis revealed that resistant isolates clustered together relative to the reference genome of E. coli K-12 MG1655. Genomic biomarkers such as gyrA, parC, CTX-M-15, OXA-1, and various multidrug efflux pumps were identified by the Comprehensive Antibiotic Resistance Database (CARD) and ResFinder as significant resistance determinants in this study. In conclusion, this study demonstrates that combining antimicrobial susceptibility testing with machine learning and genomic biomarkers is a powerful framework for predicting antimicrobial resistance in E. coli. Full article

Background: Glioblastoma (GBM) exhibits marked cellular heterogeneity and resistance to therapy. Calcium (Ca²⁺) signaling at endoplasmic reticulum (ER)–mitochondria contact sites has emerged as a key regulator of mitochondrial function and cell fate; however, its lineage-specific role and therapeutic relevance in GBM remain unclear. Methods: ITPR1 expression was analyzed using single-cell and bulk RNA sequencing (RNA-seq) datasets and validated by immunohistochemistry and survival analyses. Functional studies were conducted using genetic silencing or CRISPR-mediated activation of ITPR1, combined with DRP1 knockdown, Ca²⁺ imaging, transmission electron microscopy, co-immunoprecipitation, mitochondrial fractionation, and mitochondrial functional assays. Therapeutic efficacy was evaluated in orthotopic GBM xenograft models treated with 2-aminoethoxydiphenyl borate (2-APB), temozolomide (TMZ), or their combination. Results: ITPR1 was enriched in mesenchymal-like malignant cell states and associated with higher tumor grade, recurrence, and poor prognosis. ITPR1 knockdown suppressed GBM cell proliferation and tumor growth while promoting intrinsic apoptosis. Mechanistically, loss of ITPR1 impaired ER-to-mitochondria Ca²⁺ transfer, disrupted ER–mitochondria contacts, and altered mitochondrial ultrastructure. This was accompanied by reduced DRP1 Ser616 phosphorylation and mitochondrial recruitment, as well as decreased autophagy and mitophagy activity. Consequently, ITPR1 knockdown led to mitochondrial depolarization, increased mitochondrial reactive oxygen species (ROS) accumulation, and activation of mitochondria-dependent apoptosis. Conversely, DRP1 knockdown attenuated the mitochondrial and pro-survival effects induced by ITPR1 overexpression. In vivo, combined treatment with 2-APB and TMZ resulted in greater tumor suppression and prolonged survival compared with either treatment alone, accompanied by increased apoptosis and reduced proliferation in tumor tissues. Conclusions: ITPR1 promotes GBM progression by sustaining ER–mitochondria Ca²⁺ coupling and DRP1-dependent mitochondrial quality control, thereby maintaining mitochondrial homeostasis and cell survival. Targeting inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ signaling with 2-APB enhances the therapeutic efficacy of TMZ, suggesting that ITPR1-centered Ca²⁺ signaling may represent a potential therapeutic vulnerability in aggressive GBM. Full article

Despite prolonged viral inhibition with combination antiretroviral therapy (ART), HIV-1 survives as genetically intact, replication-capable proviruses within durable CD4+ T-cell fractions, involving central memory, transitional memory, and stem cell-like memory populations, as well as within tissue-resident compartments including lymphoid follicles and gut-associated lymphoid tissue. Reservoir stability is preserved via clonal growth of infected cells and epigenetic processes that impose proviral transcriptional silencing. As a result, current therapeutic approaches seek to either directly alter proviral survival or to improve immune-driven elimination of infected cells. At the molecular level, investigational strategies such as CRISPR–Cas9 and CRISPR–Cas12 gene-editing systems are intended to remove or induce inactivating mutations inside embedded proviral DNA, as well as alter host entrance co-receptors such as CCR5 to provide cellular resistance to infection. In addition, pharmacologic latency regulation is being studied via histone deacetylase inhibitors, protein kinase C agonists, and bromodomain inhibitors to reverse latency, along with Tat inhibitors and other transcriptional repressors aimed to persistently silence proviral expression. Moreover, immunological techniques aim to counteract inefficient endogenous antiviral defenses. Broadly neutralizing antibodies with tailored Fc-driven effector functions are under examination for both neutralization and antibody-dependent cellular cytotoxicity. Therapeutic vaccine approaches seek to elevate polyfunctional HIV-specific CD8+ T-cell responses, while adoptive cellular approaches, involving CAR-T cells aiming HIV envelope epitopes, remain in early clinical research. Immune checkpoint blockade is also being investigated to reverse T-cell depletion inside reservoir-rich tissues. Nevertheless, the key obstacles continue to be the diverse reservoir composition, restricted tissue penetration, viral escape, and safety limitations. The molecular and translational obstacles that characterize attempts toward an HIV cure must be addressed through ongoing multidisciplinary research. Full article

The WW domain-containing oxidoreductase (WWOX) gene, well-known as a tumor suppressor, also has a crucial role as a transcription factor in the developing brain. The bi-allelic loss of the WWOX gene causes a condition characterized by drug-resistant epilepsy, developmental delay, and neurological impairments, often resulting in mortality within the first year of life, known as WWOX-related epileptic encephalopathy (WOREE) syndrome (MIM: 616211). Whole Exome Sequencing (WES) analysis was performed on a female patient who died within three months of birth and was diagnosed with microcephaly, severe early-onset refractory seizures, and drug-resistant epileptic encephalopathy. WES revealed a 38 kb CNV deletion spanning WWOX exons 6–7, and a known frameshift variant in exon 8, impairing a highly clinically significant region of the encoded protein. Clinical and genetic features of reported WOREE patients with WWOX gene deletions similar to our patient were analyzed. Our case highlights the clinical heterogeneity of WWOX variants in WOREE syndrome and expands the spectrum of reported compound heterozygous deletions. Further research needs to elucidate WWOX pathophysiology and improve diagnostic and therapeutic strategies. Full article

Grape (Vitis vinifera L.) is an important fruit crop, but its production is severely threatened by ripe rot, a fungal disease caused by Colletotrichum gloeosporioides. However, V. pseudoreticulata ‘Dongan-1’ has been reported to have significant resistance to ripe rot. To investigate the molecular basis of this resistance, we employed RNA-Seq to profile transcriptome changes in the leaves and berry skins of ‘Dongan-1’ following infection. Gene Ontology (GO) enrichment analysis suggested that differentially expressed genes (DEGs) were mainly linked to stress response, cellular processes, and metabolic processes. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that DEGs in both tissues were predominantly enriched in the plant MAPK signaling pathway, peroxisome pathway, plant–pathogen interaction pathway, and plant hormone signal transduction pathway. Notably, VpCML41 was identified as a highly induced gene. Functional characterization through heterologous overexpression in Arabidopsis thaliana and transient expression in ‘Thompson Seedless’ grape leaves demonstrated that VpCML41 enhances resistance to C. gloeosporioides. This enhanced resistance involves the coordinated regulation of salicylic acid and jasmonic acid signaling cascades. Our findings provide valuable genetic resources for understanding ripe rot resistance and offer a foundation for developing resistant grape varieties. Full article

Lower-grade gliomas (LGGs) often follow a relatively protracted clinical course; however, a substantial proportion eventually undergo malignant transformation to high-grade, treatment-refractory disease. This process has traditionally been interpreted in the context of stepwise histopathologic progression and recurrent genetic alterations. Increasing evidence, however, suggests that malignant transformation is more accurately understood as an evolutionary process shaped by the interplay among epigenetic constraints, cell-state plasticity, and selective pressures. In this review, we examine current evidence supporting a model in which early LGGs, particularly isocitrate dehydrogenase (IDH)-mutant tumors, are initially maintained in relatively restricted cellular states by metabolically imposed epigenetic programs, but progressively escape these constraints under the cumulative influence of therapy, hypoxia, immune remodeling, and genomic instability. We summarize recent advances demonstrating that progression from lower-grade to high-grade disease is accompanied by cell-state transitions characterized by altered lineage identity, acquisition of stem-like features, increased proliferative capacity, and adaptation to cellular stress. We further discuss how these transitions are reinforced by microenvironmental evolution, including vascular remodeling, extracellular matrix reorganization, and changes in immune composition, thereby creating conditions that favor clonal expansion, invasion, and therapeutic resistance. Particular attention is given to longitudinal, single-cell, and spatially resolved studies, which collectively indicate that malignant transformation is not a discrete event but a continuous process of evolutionary selection and phenotypic reprogramming. Finally, we discuss the translational implications of this framework for early risk stratification, biomarker development, and mechanism-based therapeutic intervention. By reframing malignant transformation in LGGs as a process of cell-state escape under persistent selective pressure, this review aims to provide an integrated view of glioma progression and to highlight new opportunities for precision monitoring and treatment. Full article

Background/Objectives: Malaria remains a major global health burden, particularly in sub-Saharan Africa, where the recent invasion and urban expansion of Anopheles stephensi are increasing transmission risk in densely populated areas. Conventional vector control strategies, including widespread insecticide application, are progressively losing efficacy due to the rapid spread of resistance. These limitations have accelerated the development of genetic control approaches aimed at either suppressing vector populations or replacing them with genetically modified mosquitoes incapable of transmitting pathogens, with the shared objective of reducing disease transmission. For population suppression strategies, an essential component is a conditional regulatory system that enables precise control of toxic or otherwise deleterious effector proteins. The most widely used platform, the tetracycline-dependent (Tet) system, modulates gene expression in response to tetracycline. However, this system can exhibit leaky expression and variable regulation, which may compromise its reliability and limit its application in certain contexts. The dihydrofolate reductase (DHFR) destabilization domain (DD) system, developed in Drosophila, offers an alternative strategy for post-translational control of protein stability. In this system, proteins fused to a destabilization domain are rapidly degraded unless stabilized by the small molecule trimethoprim (TMP), enabling tight and reversible control. In Drosophila and prior reports, this system has been associated with relatively low fitness costs, although such effects have not been systematically evaluated in mosquitoes. Before adapting this system for mosquito genetic control, it is therefore essential to assess the impact of TMP exposure on key life-history traits. Methods: Here, we assessed the effects of varying TMP concentrations on mosquito development, survival, and reproductive output. Results: Our results demonstrate that low concentrations of TMP exposure had no detectable effects on immature development, adult survival, or reproductive output under the conditions tested, supporting the implementation of the DHFR-DD system in mosquitoes. Importantly, these effects were dose-dependent, with moderate to high TMP concentrations producing measurable impacts on mosquito fitness. Conclusions: These findings provide a foundational step toward the development of more precise and reliable conditional expression systems for genetic vector control, advancing innovative strategies to mitigate malaria transmission in high-risk regions. Full article

Background: Most patients with hepatocellular carcinoma (HCC) present with advanced disease and have limited systemic treatment options. Oxaliplatin shows clinical activity in HCC but its effectiveness is frequently curtailed by intrinsic and acquired resistance. We sought to systematically identify genetic vulnerabilities that increase oxaliplatin sensitivity in HCC. Methods: Genome-scale negative-selection CRISPR–Cas9 screens were conducted in two genetically distinct HCC cell lines (Hep3B and MHCC-97H) under low-dose oxaliplatin to discover conserved determinants of sensitivity. Selected DNA damage response (DDR) hits were validated. An oxaliplatin-resistant MHCC-97H subline was generated for transcriptomic profiling to characterize resistance-associated programs. Screen results were integrated with TCGA-LIHC expression and survival data to evaluate clinical relevance. Additionally, we analyzed bulk RNA-seq data from biopsy specimens collected from 36 HCC patients prior to initiation of hepatic arterial infusion chemotherapy (HAIC), comparing expression levels of the DDR genes between patients with objective response and non-responders. Results: Screens in both cell lines converged on DDR pathways, particularly nucleotide excision repair (NER) and the Fanconi anemia/interstrand crosslink repair network; shared sensitizers included ERCC4 (XPF), FANCE and SLX4. Validation experiments showed that disruption of representative DDR factors (POLH and XPA) synergistically increased oxaliplatin efficacy at concentrations as low as 0.5 μM. Transcriptomic analysis of the resistant MHCC-97H subline revealed coordinated upregulation of DNA repair programs, G2/M checkpoint and E2F target signatures, and epithelial–mesenchymal transition features. Integration with TCGA-LIHC data demonstrated frequent overexpression of many screen-identified DDR genes in primary HCC and an association between higher expression of selected factors and poorer patient survival. In the HAIC cohort, several DDR genes, including ATR, BRCA2, CDK7, MUS81, MUTYH, PARG, POLH, POLK and XPA, were significantly lower in the objective response group. Conclusions: DDR components represent candidate biomarkers and therapeutic targets whose inhibition may enhance oxaliplatin efficacy in HCC. Full article