Hesperetin, a flavonoid predominantly present in citrus fruits, exhibits significant intervention effects on both the initiation and progression of gastric cancer. However, the specific mechanisms underlying this effect remain unclear.

Ovarian cancer (OC) often presents at advanced stages with poor prognosis. Although poly(ADP-ribose) polymerase inhibitors (PARPi) offer clinical benefits, resistance remains a major challenge. This study investigates the role of KLF5 in regulating OC cell stemness and contributing to PARPi resistance.

The ATP-binding cassette (ABC) transporter family is one of the largest and oldest protein families and encodes a class of transmembrane transporter proteins that transport substances in living organisms. Panax ginseng is a traditional Chinese herbal medicine, and its main active ingredient is ginsenoside, a secondary metabolite. Transportation and accumulation of secondary metabolites require the participation of ABC transporter proteins. In this study, we performed a genome-wide identification and expression analysis of the ginseng ABC transporter family using bioinformatics tools. Analysis of 106 PgABC genes showed that they were classified into seven subfamilies, among which ABCG was the most abundant subfamily. Chromosomal localization and covariance analyses showed that PgABC genes were unevenly distributed on chromosomes and that tandem repeat sequences existed. Tissue expression analyses revealed that PgABC expression was tissue-specific in ginseng. Cis-acting element analyses showed that PgABC genes responded to induction by hormones such as methyl jasmonate (MeJA). Subsequent qRT-PCR analysis of MeJA-treated ginseng adventitious roots revealed dynamic expression changes in nine PgABC genes, with PgABC14, PgABC18, and PgABC24-01 showing significant upregulation. The identification and analysis of the ABC transporter family in ginseng lays a theoretical foundation for the subsequent study of the function of the ABC gene family in ginseng and provides a theoretical basis for the study of ABC transporter proteins in other medicinal plant species.

The search for more effective and safer cancer therapies has led to an increasing interest in combination treatments that use well-established agents. Here we explore the potential of cannabidiol (CBD), a compound derived from cannabis, to enhance the anticancer effects of etoposide in non-small cell lung cancer (NSCLC). Although CBD is primarily used to manage childhood epilepsy, its broader therapeutic applications are being actively investigated, particularly in oncology. Our results revealed that, among various tested chemotherapeutic drugs, etoposide showed the most significant reduction in NSCLC cell viability when combined with CBD. To understand this synergistic effect, we conducted extensive transcriptomic and proteomic profiling, which showed that the combination of CBD and etoposide upregulated genes associated with autophagic cell death while downregulating key oncogenes known to drive tumor progression. This dual effect on cell death and oncogene suppression was mediated by inactivation of the PI3K-AKT-mTOR signaling pathway, a crucial regulator of cell growth and survival, and was found to be dependent on the p53 status. Interestingly, our analysis revealed that this combination therapy did not rely on traditional cannabinoid receptors or transient receptor potential cation channels, indicating that CBD exerts its anticancer effects through novel, noncanonical mechanisms. The findings suggest that the combination of CBD with etoposide could represent a groundbreaking approach to NSCLC treatment, particularly in cases where conventional therapies fail. By inducing autophagic cell death and inhibiting oncogenic pathways, this therapeutic strategy offers a promising new avenue for enhancing treatment efficacy in NSCLC, especially in tumors with p53 function.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and fatal malignancy, although gemcitabine is administered as a single or combined therapeutic agent. Our previous study demonstrated that ANP32E overexpression promoted PDAC cell proliferation. However, whether it affects treatment outcome and clinical prognosis is still unclear. In the present study, we aimed to determine whether ANP32E is negatively associated with the treatment outcome of gemcitabine.

Cisplatin resistance poses a substantial barrier to the successful treatment of advanced endometrial cancer. Glucose deprivation in the tumor microenvironment, resulting from inadequate vascularization and rapid proliferation of cancer cells, may promote chemoresistance by modifying cellular metabolism and survival pathways. This study aimed to elucidate how glucose deprivation induces cisplatin resistance in endometrial cancer cells, focusing on the role of solute carrier family 7 member 11 (SLC7A11, xCT). The endometrial cancer cell lines HEC-1A and AN3CA were cultured under glucose-deprived and glucose-supplemented conditions. Cisplatin half-maximal inhibitory concentration (IC50) values, SLC7A11 expression, and reactive oxygen species (ROS) levels were assessed using cell proliferation assays, real-time PCR, Western blotting, and fluorescence assays. SLC7A11 was inhibited using small interfering RNA (siRNA) knockdown and the selective inhibitor HG106. Cisplatin-resistant cell lines were generated to evaluate the effect of SLC7A11 inhibition. Glucose deprivation significantly decreased cisplatin sensitivity and increased cisplatin IC50 values (P < 0.05). This reduction in sensitivity was accompanied by upregulation of SLC7A11 expression and decreased ROS levels (P < 0.05). Inhibition of SLC7A11, either by siRNA or HG106, increased cisplatin sensitivity and ROS production, even in cisplatin-resistant cells (P < 0.05). This effect was reversible with the antioxidant N-acetylcysteine. These findings demonstrate that glucose deprivation induces cisplatin resistance in endometrial cancer cells by upregulating SLC7A11, leading to reduced ROS levels and enhanced cell survival. Targeting SLC7A11 restores cisplatin sensitivity by elevating ROS production, even in cisplatin-resistant cells. The findings suggest that SLC7A11 is a promising therapeutic target for overcoming chemoresistance in endometrial cancer, potentially improving treatment outcomes and patient survival.

Beta-hemoglobinopathies such as beta-thalassemia and sickle cell disease are severe genetic blood disorders affecting the beta globin chain of haemoglobin A (α2β2). Activation of delta globin, the non-alpha globin of HbA2 (α2δ2), could represent a possible approach to improve the clinical severity of these pathologies. Notably, the therapeutic potential of delta globin has been demonstrated in previous studies using a mouse model of beta-thalassemia and sickle cell disease. The present study evaluated delta globin gene activation by small molecules in erythroid cells isolated from transgenic murine foetal liver. A screening of 119 molecules, selected for their potential in drug repurposing, was performed without prior selection based on specific pathways of interest. Three candidates-Nexturastat, Stattic and Palbociclib-were found to have high efficacy on delta globin expression. Palbociclib also proved effective in increasing gamma globin expression. All of these compounds have pharmacokinetic profiles that are beneficial for clinical application, providing potential inducer agents of HbA2 that could have therapeutic effects in the treatment of beta-hemoglobinopathies.

Antibiotic combinations can slow down resistance development and/or achieve synergistic therapeutic effects. In this study, we observed that a combined use of ceftazidime-avibactam (CZA) with azithromycin effectively repressed CZA resistance development in Pseudomonas aeruginosa. Transcriptome analysis revealed that subinhibitory concentrations of azithromycin reduced the expression of genes involved in stress-induced mutagenesis, including the stress response sigma factor rpoS. Interestingly, ribosome profiling revealed global redistribution of ribosomes by azithromycin, among which ribosome stalling was significantly intensified near the 5´ terminus of the rpoS mRNA. Further DNA mutational analysis revealed that azithromycin represses the translation of rpoS through its 5´-terminal rare codons, which in turn reduced its transcription. These in vitro observations have been recapitulated in vivo where azithromycin-repressed CZA resistance development when P. aeruginosa was passaged in mice. Overall, our study revealed the molecular mechanism of azithromycin-mediated repression of antibiotic resistance development, providing a promising antibiotic combination for the treatment of P. aeruginosa infections.IMPORTANCEAntibiotic resistance, a global public health challenge, demands the development of novel antibiotics and therapeutic strategies. Ceftazidime-avibactam (CZA) is a combination of a β-lactam antibiotic with a β-lactamase inhibitor that is effective against various gram-negative bacteria such as Pseudomonas aeruginosa. However, clinical CZA-resistant isolates have been reported. Here, we found that combining CZA with azithromycin can effectively suppress the development of resistance in P. aeruginosa in vitro and in vivo. Moreover, we found that azithromycin represses the translation initiation of rpoS through its 5´-terminal rare and less frequent codons, thereby subsequently reducing the mutational frequency of CZA resistance. Therefore, our work provides a promising antibiotic combination for the treatment of P. aeruginosa infections.

The peroxiredoxin (PRDX) family, also known as the peroxidase family, consists of six members that participate in a variety of essential bio-processes in carcinogenesis. However, their molecular role in lung adenocarcinoma (LUAD) has not been systematically explored. Using bioinformatic tools, we systematically analyzed the expression, prognostic value and drug sensitivity of the PRDX gene family members in LUAD. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the expression of PRDX1 in both LUAD tissues and cells. Cell Counting Kit-8 (CCK-8) assay was applied to detect the half-maximal inhibitory concentration (IC50) of osimertinib in LUAD. A series of cellular drug assays, including 5-Ethynyl-2'-deoxyuridine (EdU), colony formation, and apoptosis assays, were performed to explore the correlation of PRDX1 with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sensitivity by using EGFR-mutant and wild-type LUAD cell lines. Among all the PRDX family members, PRDX1 has a promising prognostic value and is associated with EGFR mutations, as verified by experiments conducted on collected LUAD specimens. In addition, pathway enrichment analysis suggested that PRDX1 expression positively correlated with DNA repair, which is often considered to be inextricably linked to drug resistance in tumor cells. Thus, we validated the correlation between PRDX1 and EGFR-TKI sensitivity through a series of in vitro experiments and found that PRDX1 inhibition along with osimertinib treatment resulted in synergistic inhibition of tumor growth. Moreover, we found that PRDX1 was negatively correlated with the immune infiltration of dendritic cells (DCs) in the tumor microenvironment (TME) of LUAD, further suggesting an oncogenic role of PRDX1. This study demonstrates that high PRDX1 expression could be a potential diagnostic and prognostic marker of LUAD, and the strategy of PRDX1 knockdown provides new insights into improving the therapeutic sensitivity of EGFR-TKI in patients with LUAD.

Chemotherapeutic drugs, like cisplatin, function by damaging genomic DNA, thus inducing cell apoptosis. Cancer cells can enhance their DNA repair capacity, leading to chemotherapeutic resistance. Nucleotide excision repair (NER) involves repairing DNA adducts and crosslinks caused by chemotherapeutic agents. Transforming growth factor-beta (TGF-β) pathway contributes to carcinogenesis, DNA repair alteration, and chemoresistance. However, the connection between TGF-β pathway, NER function alteration, and resistance to cisplatin therapy remains elusive. Therefore, the objective of current study was to fill this gap by assessing the impact of TGF-β inhibition and activation on cisplatin-induced antiproliferation, apoptosis, and DNA damage using the MTT assay, flow cytometry analysis, and COMET assay, respectively. Four NER genes, XPA, XPB, XPC, and XPF, were measured using Real-time Polymerase Chain Reaction (qPCR). MDA-MB-231 cell line was utilized as a model of breast cancer. Blockade of the TGF-β pathway strengthened cisplatin cytotoxicity, whereas induction of the TGF-β pathway suppressed cisplatin cytotoxicity. In cisplatin-treated breast cancer cells, DNA damage significantly increased upon the TGF-β pathway inhibition. Conversely, cisplatin-induced DNA damage decreased significantly upon TGF-β pathway stimulation. Finally, cisplatin caused an overexpression of the four NER genes which was curtailed and augmented by TGF-β inhibition and stimulation, respectively. Overall, this study presented evidence of the impact exerted by TGF-β pathway on NER and cisplatin sensitivity of breast cancer cells.

Background: Doxorubicin (DOX) is a widely employed chemotherapeutic drug, while its clinical use is limited by the lethal cardiotoxicity. Previous studies highlighted the critical role of cardiomyocyte ferroptosis in the pathogenesis of DOX-induced cardiotoxicity (DIC). Androgen-induced gene 1 (AIG1) is perceived as a key regulator of oxidative stress-mediated cell death. Nonetheless, it remains elusive whether AIG1 is involved in the progression of DOX-induced cardiomyocyte ferroptosis and cardiotoxicity. Methods: C57BL/6 male mice were repeatedly administrated with DOX at an accumulative dosage of 20 mg/kg to establish a chronic DIC model. Global AIG1 knockout mice and AAV9-mediated cardiac-specific AIG1 knockdown or overexpression mice were utilized to evaluate the precise role of AIG1 in DIC. Additionally, the effects of AIG1 on cardiomyocyte ferroptosis were further investigated following DOX stimulation. Results: Ferroptosis played a pivotal role in DIC in both in vivo and in vitro settings. DOX exposure significantly reduced AIG1 expression levels in cardiomyocytes. Global AIG1 knockout or cardiac-specific AIG1 knockdown mice exhibited deteriorated cardiac function, adverse cardiac remodeling following DOX insult. Moreover, AIG1 deficiency aggravated DOX-evoked ferroptosis and oxidative stress in cardiomyocytes, whereas cardiac-specific overexpression of AIG1 conferred the protective effects manifested by the inhibition of cardiomyocyte ferroptosis and improvements in cardiac performance and remodeling under DOX challenge. Mechanistically, AIG1 directly interacted with the Pirh2 E3 ubiquitin ligase to promote the ubiquitination of p53, a key protein governing ferroptosis during DIC, thereby accelerating its degradation. Cardiac-specific Pirh2 knockdown markedly exacerbated DOX-induced ferroptosis by enhancing p53 activity in cardiomyocytes. Furthermore, the pharmacological administration of a highly selective p53 inhibitor PFT-α effectively ameliorated DIC in mice by inhibiting cardiomyocyte ferroptosis and substantially abrogated the deleterious cardiac effects associated with AIG knockout under DOX challenge. Conclusion: Our findings defined the critical cardioprotective role of AIG1 in DIC by alleviating cardiomyocyte ferroptosis in a Pirh2/p53 axis-dependent manner. Targeting the novelly identified AIG1-Pirh2-p53 signaling axis presents a promising approach to prevent DIC.

Retinoblastoma (Rb) is a rare cancer, yet it is the most common eye tumor in children. It can occur in either a familial or sporadic form, with the sporadic variant being more prevalent, though its downstream effects on epigenetic markers remain largely unclear. Currently, the treatment for retinoblastoma typically involves aggressive chemotherapy and surgical resection. The identification of specific epigenetic characteristics of non-hereditary (sporadic) Rb has led to the development of advanced, high-throughput methods to explore its epigenetic profile. Our previous research demonstrated that treatment with the demethylating agent 5-Aza-2'-deoxycytidine (decitabine; DAC) induced cell cycle arrest and apoptosis in a well-characterized retinoblastoma model (WERI-Rb-1). Our analysis of time-dependent gene expression in WERI-Rb-1 cells following DAC exposure has led to the development of testable hypotheses to further investigate the epigenetic impact on the initiation and progression of retinoblastoma tumors.

We present an atlas of genes that respond to thyroid hormone in the adult mouse mediobasal hypothalamus. Based on droplet-based single nuclei RNA-seq method and batch transcriptome analyses, the atlas lists putative target genes of the hormone nuclear receptors in 20 different types of neuronal and glial cells. The transcriptional regulation of these genes varies extensively across neuronal and glial cell types. However, while astrocytes appear to be highly sensitive to thyroid hormone stimulation, differentiated oligodendrocytes are relatively insensitive. This atlas is expected to promote future investigations into the molecular and cellular mechanisms that underlie the numerous functions of thyroid hormone in the hypothalamic circuits.

Toona fargesii A. Chev. (T. fargesii), a precious tree with timber and medicinal properties, belongs to the Toona genus of the Meliaceae family. It is an endangered species in China, owing to various issues including the concerns about the drought aspect. KNOXs (knotted-like homeoboxes), a subset of TALE transcription factors, play pivotal roles in development and abiotic stress including drought resistance. The recent publication of the T. fargesii genome, indicating a specific whole-genome duplication (WGD) event in the Toona genus, serves as a valuable resource for uncovering the role of KNOX genes in T. fargesii. Here, genome-wide analysis including identification, synteny and duplication of KNOX genes was conducted to unveil their characterization and evolution. Moreover, gene structures, protein-protein interaction (PPI), subcellular localizations and expression patterns were also examined to verify KNOX genes with respect to drought response and development in T. fargesii. Generally, 21 putative TfKNAT (orthologs of KNAT) genes were identified and classified into three subfamilies. Intriguingly, most of TfKNAT gene possessed a paralog on another chromosome exhibiting high collinearity and similarities in chromosome regional assignments, sequences, structures, cis-elements, subcellular localizations and expression patterns. They diverged approximately 4.2 to 8.4 million years ago (MYA) approaching to the specific WGD (22.1 ~ 50.1 MYA) which may predominantly drive the family expansion. More importantly, the cis-elements contained many ABA-responsive elements strongly associated with drought stress, especially three TfKNAT3/4 genes, and PPI analysis suggested that TfKNAT3/4 could interact with proteins related to the drought. Indeed, the expression of three TfKNAT3/4 members sharply increased and then gradually decreased with prolonged PEG stress duration. Additionally, the ABA treatment significantly induced three TfKNAT3/4 genes expression also strengthened their involvement in the drought stress. Collectively, our findings highlight the significance of the TfKNAT family and the potential role of TfKNAT3/4 in drought resistance of T. fargesii.

There is a tremendous upsurge in lung cancer incidences due to changing lifestyles and other environmental risk factors. Unfortunately, the use of clinical therapeutics is causing serious side effects and drug-resistant tumors. Taking account of the severity of lung cancer malignancy and the pressing need for natural therapeutics, we investigated the anticancer potential of bixin in A549, pulmonary alveolar adenocarcinoma cell lines meticulously for the first time. Bixin is an apocarotenoid present in the seed arils of Bixa orellana known for its remarkable coloring utilities and high medicinal value. Here, we identified the cytotoxic and anti-migratory nature of bixin through MTT and scratch assay. Bixin also induced characteristic apoptotic morphological changes in cells which were distinguished through 4',6-diamidino-2-phenylindole (DAPI), and Acridine orange/Ethidium bromide (AO/EB) labeling. Bixin induced the mitochondrion-associated intrinsic apoptosis in A549 cells as evidenced in mitochondrial membrane potential assay, apoptosis assay, cell cycle analysis, and caspase assays. The relative gene expression studies proved that the bixin upregulated BAX, and downregulated BCL-2 and Cyclin D1. The in-silico analyses, molecular docking and molecular dynamics simulation underlined the interaction features of bixin and targeted proteins.

Ovarian cancer remains the most lethal gynecological malignancy, largely owing to its chemotherapy resistance and high recurrence rate. Emerging evidence has linked the aberrant expression of SOX2, a transcription factor that is important in the development and maintenance of stem cell state, with chemoresistance and poor prognosis of ovarian cancer patients. In this study, we aimed to elucidate the mechanisms that drive aberrant SOX2 expression in ovarian cancer cells. By examining multiple ovarian cancer cell lines and a panel of clinical tumor samples, we observed a broad overexpression of SOX2 in ovarian cancer cell lines and tumors. To identify signaling pathway(s) that drives SOX2 overexpression in ovarian cancer cells, we screened a set of small-molecule kinase inhibitors that target 30 major cellular kinases. Among the top hits identified are AKT inhibitors. We demonstrated that inhibition or knockdown of AKT1 can drastically downregulate SOX2 protein level, impairs the growth and stemness of SOX2-positive ovarian cancer cells, and markedly sensitize SOX2-positive ovarian cancer cells to platinum drugs. Mechanically, we found that AKT1 drives SOX2 overexpression primarily by enhancing its protein stability and does so by phosphorylating SOX2 at threonine 116. Altogether, our study reveals an underlying mechanism that drives SOX2 overexpression in ovarian cancer and underscores pharmacological inhibition of AKT1 as a potential therapeutic strategy to sensitize SOX2-positive ovarian cancer to platinum drugs.

Genomic variation drives phenotypic diversity, including individual differences in drug response. While coding polymorphisms linked to drug efficacy and adverse reactions are well characterized, the contribution of noncoding regulatory elements remains underexplored. Using CAGE (Cap Analysis of Gene Expression), profiling transcription initiations of mRNAs and enhancer RNAs, we identify candidate cis-regulatory elements (CREs) and assessed their activities simultaneously in HepG2 cells expressing the drug-responsive transcription factor pregnane X receptor (PXR). Comparison with GWAS data reveals strong enrichment of the drug-induced CREs near variants associated with bilirubin and vitamin D levels. Among those bound by PXR in primary hepatocytes, we identify enhancers of UGT1A1, TSKU, and CYP24A1 and functional alleles that alter regulatory activities. We also find that TSKU influences expression of vitamin D-metabolizing enzymes. This study expands the landscape of PXR-mediated regulatory elements and uncovers noncoding variants impacting drug response, providing insights into the genomic basis of adverse drug reactions.

Despite aggressive therapy, glioblastoma (GBM) recurs in almost all patients and treatment options are very limited. Despite our growing understanding of how cellular transitions associate with relapse in GBM, critical gaps remain in our ability to block these molecular changes and treat recurrent disease. In this study we combine computational biology, forward-thinking understanding of miRNA biology and cutting-edge nucleic acid delivery vehicles to advance targeted therapeutics for GBM. Computational analysis of RNA sequencing from clinical GBM specimens identified TGFβ type II receptor (TGFBR2) as a key player in the mesenchymal transition associated with worse outcome in GBM. Mechanistically, we show that elevated levels of TGFBR2 is conducive to reduced temozolomide (TMZ) sensitivity. This effect is, at least partially, induced by stem-cell driving events coordinated by the reprogramming transcription factors Oct4 and Sox2 that lead to open chromatin states. We show that blocking TGFBR2 via molecular and pharmacological approaches decreases stem cell capacity and sensitivity of clinical recurrent GBM (rGBM) isolates to TMZ in vitro. Network analysis uncovered miR-590-3p as a tumor suppressor that simultaneously inhibits multiple oncogenic nodes downstream of TGFBR2. We also developed novel biodegradable lipophilic poly(β-amino ester) nanoparticles (LiPBAEs) for in vivo microRNA (miRNAs) delivery. Following direct intra-tumoral infusion, these nanomiRs efficiently distribute through the tumors. Importantly, miR-590-3p nanomiRs inhibited the growth and extended survival of mice bearing orthotopic human rGBM xenografts, with an apparent 30% cure rate. These results show that miRNA-based targeted therapeutics provide new opportunities to treat rGBM and bypass the resistance to standard of care therapy.

Potato late blight is an important disease in potato production, which causes serious damage. Salicylic acid (SA) is a plant hormone involved in the regulation of potato (Solanum tuberosum) resistance to Phytophthora infestans. In this study, it was found that exogenous methyl salicylate (MeSA) treatment could significantly enhance the resistance of potato to P. infestans. RNA-seq results confirmed that SA was important for potato resistance to P. infestans. Salicylic acid binding protein 2 (SABP2) is a member of α/β hydrolase family, which can convert MeSA into SA to regulate the steady state of SA in plants. StSABP2 protein was obtained through prokaryotic expression, and enzymatic analysis in vitro confirmed that StSABP2 could transform MeSA into SA. In order to explore the function of StSABP2 in the process of plant resistance to P. infestans, we carried out virus-mediated gene silencing of StSABP2 in potato and transiently expressed StSABP2 in tobacco. The results showed that StSABP2 positively regulated plant resistance to P. infestans, and this process was achieved by mediating the transcription of SA signal and defence-related genes. Then we screened for the upstream regulator of StSABP2. The results of double luciferase and yeast one-hybrid analysis showed that StNAC2 could activate the transcription of StSABP2. The StNAC2-StSABP2 module regulated potato resistance to P. infestans by positively mediating the SA pathway. This study provides a new idea for improving host resistance to potato late blight by regulating the SA signal in potato and provides germplasm resources for potato resistance breeding.

Fusarium oxysporum (F. oxysporum) is one of the main pathogenic fungus causing maize ear rot. In this study, the aims were to screen highly effective pesticides for F. oxysporum, reduce peasants' misunderstandings about pesticide application, improve disease control levels, and enhance economic efficiency. The toxicity of seven fungicides (carbendazim, pyraclostrobin, epoxiconazole, tricyclazole, azoxystrobin, difenoconazole, quintozene) on F. oxysporum were determined by the mycelium growth rate and the spore germination method, and single and compound fungicides with effective inhibitory effects on mycelial growth were screened. The RT-qPCR method was used to detect the expression levels of chitin synthetase V (ChsV), folate uptake block T (FUBT), superoxide dismutase (SOD), and peroxidase dismutase (POD) genes in pathogenic bacteria treated with the selected agents and combination of fungicides. The results showed that all seven fungicides had inhibitory effects on mycelial growth hyphae and spore germination of F. oxysporum. Epoxiconazole had the strongest inhibitory effect on mycelium growth and spore germination of F. oxysporum, with effective concentrations (EC50) of 0.047 and 0.088 μg/mL, respectively. The combination of pyraclostrobin and difenoconazole (P&D, combined at a mass ratio of 7:3) had the best inhibitory effect, with an EC50 of 0.094 μg/mL and an SR of 2.650. Epoxiconazole and the combination P&D could inhibit mycelial growth and spore germination by down-regulating ChsV, FUBT, and POD, causing oxidative stress in F. oxysporum, and reducing the occurrence of maize ear rot.