Autophagy as a targeted therapeutic approach for skin cancer: Evaluating natural and synthetic molecular interventions.

Skin cancer, a prevalent malignancy worldwide, poses significant health concerns owing to its increasing incidence. Autophagy, a natural cellular process, is a pivotal event in skin cancer and has advantageous and detrimental effects. This duality has prompted extensive investigations into medical interventions targeting autophagy modulation for their substantial therapeutic potential. This systematic review aimed to investigate the relationship between skin cancer and autophagy and the contribution and mechanism of autophagy modulators in skin cancer. We outlined the effectiveness and safety of targeting autophagy as a promising therapeutic strategy for the treatment of skin cancer. This comprehensive review identified a diverse array of autophagy modulators with promising potential for the treatment of skin cancer. Each of these compounds demonstrates efficacy through distinct physiological mechanisms that have been elucidated in detail. Interestingly, findings from a literature search indicated that none of the natural, synthetic, or semisynthetic compounds exhibited notable adverse effects in either human or animal models. Consequently, this review offers novel mechanistic and therapeutic perspectives on the targeted modulation of autophagy in skin cancer.

Prognosis of colorectal cancer, prognostic index of immunogenic cell death associated genes in response to immunotherapy, and potential therapeutic effects of ferroptosis inducers.

Introduction: This study leverages bioinformatics and medical big data to integrate datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), providing a comprehensive overview of immunogenic cell death (ICD)-related gene expression in colorectal cancer (CRC). The research aims to elucidate the molecular pathways and gene networks associated with ICD in CRC, with a focus on the therapeutic potential of cell death inducers, including ferroptosis agents, and their implications for precision medicine. Methods: We conducted differential expression analysis and utilized advanced bioinformatic techniques to analyze ICD-related gene expression in CRC tissues. Unsupervised consensus clustering was applied to categorize CRC patients into distinct ICD-associated subtypes, followed by an in-depth immune microenvironment analysis and single-cell RNA sequencing to investigate immune responses and cell infiltration patterns. Experimental validation was performed to assess the impact of cell death inducers on ICD gene expression and their interaction with ferroptosis inducers in combination with other clinical drugs. Results: Distinct ICD gene expression profiles were identified in CRC tissues, revealing molecular pathways and intricate gene networks. Unsupervised consensus clustering refined the CRC cohort into unique ICD-associated subtypes, each characterized by distinct clinical and immunological features. Immune microenvironment analysis and single-cell RNA sequencing revealed significant variations in immune responses and cell infiltration patterns across these subtypes. Experimental validation confirmed that cell death inducers directly affect ICD gene expression, highlighting their therapeutic potential. Additionally, combinatorial therapies with ferroptosis inducers and clinical drugs were shown to influence drug sensitivity and resistance in CRC. Discussion: Our findings underscore the importance of ICD-related genes in CRC prognosis and therapeutic targeting. The study provides actionable insights into the efficacy of cell death-inducing therapies, particularly ferroptosis inducers, and their regulatory mechanisms in CRC. These discoveries support the development of precision medicine strategies targeting ICD genes and offer valuable guidance for translating these therapies into clinical practice, with the potential to enhance CRC treatment outcomes and patient survival.

In Vitro Models of Cardiovascular Calcification.

Cardiovascular calcification, characterized by hydroxyapatite deposition in the arterial wall and heart valves, is associated with high cardiovascular morbidity and mortality. Cardiovascular calcification is a hallmark of aging but is frequently seen in association with chronic diseases, such as chronic kidney disease (CKD), diabetes, dyslipidemia, and hypertension in the younger population as well. Currently, there is no therapeutic approach to prevent or cure cardiovascular calcification. The pathophysiology of cardiovascular calcification is highly complex and involves osteogenic differentiation of various cell types of the cardiovascular system, such as vascular smooth muscle cells and valve interstitial cells. In vitro cellular and ex vivo tissue culture models are simple and useful tools in cardiovascular calcification research. These models contributed largely to the discoveries of the numerous calcification inducers, inhibitors, and molecular mechanisms. In this review, we provide an overview of the in vitro cell culture and the ex vivo tissue culture models applied in the research of cardiovascular calcification.

Pyroptosis and chemical classification of pyroptotic agents.

Pyroptosis, as a lytic-inflammatory type of programmed cell death, has garnered considerable attention due to its role in cancer chemotherapy and many inflammatory diseases. This review will discuss the biochemical classification of pyroptotic inducers according to their chemical structure, pyroptotic mechanism, and cancer type of these targets. A structure-activity relationship study on pyroptotic inducers is revealed based on the surveyed pyroptotic inducer chemotherapeutics. The shared features in the chemical structures of current pyroptotic inducer agents were displayed, including an essential cyclic head, a vital linker, and a hydrophilic tail that is significant for π-π interactions and hydrogen bonding. The presented structural features will open the way to design new hybridized classes or scaffolds as potent pyroptotic inducers in the future, which may represent a solution to the apoptotic-resistance dilemma along with synergistic chemotherapeutic advantage.

Ferroptosis and oral squamous cell carcinoma: connecting the dots to move forward.

Oral squamous cell carcinoma (OSCC) is an aggressive disease whose incomplete biological comprehension contributes to the inappropriate clinical management and poor prognosis. Thus, the identification of new promising molecular targets to treat OSCC is of paramount importance. Ferroptosis is a regulated cell death caused by the iron-dependent accumulation of reactive oxygen species and the consequent oxidative damage of lipid membranes. Over the last five years, a growing number of studies has reported that OSCC is sensitive to ferroptosis induction and that ferroptosis inducers exert a remarkable antitumor effect in OSCC, even in those displaying low response to common approaches, such as chemotherapy and radiotherapy. In addition, as ferroptosis is considered an immunogenic cell death, it may modulate the immune response against OSCC. In this review, we summarize the so far identified ferroptosis regulatory mechanisms and prognostic models based on ferroptosis-related genes in OSCC. In addition, we discuss the perspective of inducing ferroptosis as a novel strategy to directly treat OSCC or, alternatively, to improve sensitivity to other approaches. Finally, we integrate data emerging from the research studies, reviewed here, through in silico analysis and we provide a novel personal perspective on the potential interconnection between ferroptosis and autophagy in OSCC.

Photobiomodulation Dose-Response on Adipose-Derived Stem Cell Osteogenesis in 3D Cultures.

Osteoporosis and other degenerative bone diseases pose significant challenges to global healthcare systems due to their prevalence and impact on quality of life. Current treatments often alleviate symptoms without fully restoring damaged bone tissue, highlighting the need for innovative approaches like stem cell therapy. Adipose-derived mesenchymal stem cells (ADMSCs) are particularly promising due to their accessibility, abundant supply, and strong differentiation potential. However, ADMSCs tend to favor adipogenic pathways, necessitating the use of differentiation inducers (DIs), three-dimensional (3D) hydrogel environments, and photobiomodulation (PBM) to achieve targeted osteogenic differentiation. This study investigated the combined effects of osteogenic DIs, a fast-dextran hydrogel matrix, and PBM at specific wavelengths and fluences on the proliferation and differentiation of immortalized ADMSCs into osteoblasts. Near-infrared (NIR) and green (G) light, as well as their combination, were used with fluences of 3 J/cm2, 5 J/cm2, and 7 J/cm2. The results showed statistically significant increases in alkaline phosphatase levels, a marker of osteogenic differentiation, with G light at 7 J/cm2 demonstrating the most substantial impact on ADMSC differentiation. Calcium deposits, visualized by Alizarin red S staining, appeared as early as 24 h post-treatment in PBM groups, suggesting accelerated osteogenic differentiation. ATP luminescence assays indicated increased proliferation in all experimental groups, particularly with NIR and NIR-G light at 3 J/cm2 and 5 J/cm2. MTT viability and LDH membrane permeability assays confirmed enhanced cell viability and stable cell health, respectively. In conclusion, PBM significantly influences the differentiation and proliferation of hydrogel-embedded immortalized ADMSCs into osteoblast-like cells, with G light at 7 J/cm2 being particularly effective. These findings support the combined use of 3D hydrogel matrices and PBM as a promising approach in regenerative medicine, potentially leading to innovative treatments for degenerative bone diseases.

A potential therapeutic strategy based on acute oxidative stress induction for wild-type NRF2/KEAP1 lung squamous cell carcinoma.

Extensive efforts have been conducted in the search for new targetable drivers of lung squamous cell carcinoma (LUSC); to date, however, candidates remain mostly unsuccessful. One of the oncogenic pathways frequently found to be active in LUSC is NFE2L2 (NRF2 transcription factor), the levels of which are regulated by KEAP1. Mutations in NFE2L2 or KEAP1 trigger NRF2 activation, an essential protector against reactive oxygen species (ROS). We hypothesized that the frequency of NRF2 activation in LUSC (∼35 %) may reflect a sensitivity of LUSC to ROS. Results from this study reveal that whereas tumors containing active forms of NRF2 were protected, ROS induction in wild-type NFE2L2/KEAP1 LUSC cells triggered ferroptosis. The mechanism of ROS action in normal-NRF2 LUSC cells involved transient NRF2 activation, miR-126-3p/miR-126-5p upregulation, and reduction of p85ß and SETD5 levels. SETD5 levels reduction triggered pentose pathway gene levels increase to toxic values. Simultaneous depletion of p85ßPI3K and SETD5 triggered LUSC cell death, while p85ßPI3K and SETD5 overexpression rescued survival of ROS-treated normal-NRF2 LUSC cells. This shows that the cascade involving NRF2 > miR-126-3p, miR-126-5p > p85ßPI3K and SETD5 is responsible for ROS-induced cell death in normal-NRF2 LUSC. Transient ROS-induced cell death is shown in 3D spheroids, patient-derived organoids, and in xenografts of wild-type NFE2L2/KEAP1 LUSC cells, supporting the potential of acute local ROS induction as a therapeutic strategy for LUSC patients with normal-NRF2.

The Bioactive Gamma-Oryzanol from Oryza sativa L. Promotes Neuronal Differentiation in Different In Vitro and In Vivo Models.

Gamma-oryzanol (ORY), found in rice (Oryza sativa L.), is a mixture of ferulic acid esters with triterpene alcohols, well-known for its antioxidant and anti-inflammatory properties. Our past research demonstrated its positive impact on cognitive function in adult mice, influencing synaptic plasticity and neuroprotection. In this study, we explored whether ORY can exert neuro-differentiating effects by using different experimental models. For this purpose, chemical characterization identified four components that are most abundant in ORY. In human neuroblastoma cells, we showed ORY's ability to stimulate neurite outgrowth, upregulating the expression of GAP43, BDNF, and TrkB genes. In addition, ORY was found to guide adult mouse hippocampal neural progenitor cells (NPCs) toward a neuronal commitment. Microinjection of ORY in zebrafish Tg (-3.1 neurog1:GFP) amplified neurog1-GFP signal, islet1, and bdnf mRNA levels. Zebrafish nrf2a and nrf2b morphants (MOs) were utilized to assess ORY effects in the presence or absence of Nrf2. Notably, ORY's ability to activate bdnf was nullified in nrf2a-MO and nrf2b-MO. Furthermore, computational analysis suggested ORY's single components have different affinities for the Keap1-Kelch domain. In conclusion, although more in-depth studies are needed, our findings position ORY as a potential source of bioactive molecules with neuro-differentiating potential involving the Nrf2 pathway.

GQIcombi application to subdue glioma via differentiation therapy.

Current therapy protocols fail to cure high-grade gliomas and prevent recurrence. Therefore, novel approaches need to be developed. A re-programing of glioma cell fate is an alternative attractive way to stop tumor growth. The two-step protocol applies the antiproliferative GQ bi-(AID-1-T) and small molecule inducers with BDNF to trigger neural differentiation into terminally differentiated cells, and it is very effective on GB cell cultures. This original approach is a successful example of the "differentiation therapy". To demonstrate a versatility of this approach, in this publication we have extended a palette of cell cultures to gliomas of II, III and IV Grades, and proved an applicability of that version of differential therapy for a variety of tumor cells. We have justified a sequential mode of adding of GQIcombi components to the glioma cells. We have shown a significant retardation of tumor growth after a direct injection of GQIcombi into the tumor in rat brain, model 101/8. Thus, the proposed strategy of influencing on cancer cell growth is applicable to be further translated for therapy use.

Glycolipids biosurfactants production using low-cost substrates for environmental remediation: progress, challenges, and future prospects.

The production of renewable materials from alternative sources is becoming increasingly important to reduce the detrimental environmental effects of their non-renewable counterparts and natural resources, while making them more economical and sustainable. Chemical surfactants, which are highly toxic and non-biodegradable, are used in a wide range of industrial and environmental applications harming humans, animals, plants, and other entities. Chemical surfactants can be substituted with biosurfactants (BS), which are produced by microorganisms like bacteria, fungi, and yeast. They have excellent emulsifying, foaming, and dispersing properties, as well as excellent biodegradability, lower toxicity, and the ability to remain stable under severe conditions, making them useful for a variety of industrial and environmental applications. Despite these advantages, BS derived from conventional resources and precursors (such as edible oils and carbohydrates) are expensive, limiting large-scale production of BS. In addition, the use of unconventional substrates such as agro-industrial wastes lowers the BS productivity and drives up production costs. However, overcoming the barriers to commercial-scale production is critical to the widespread adoption of these products. Overcoming these challenges would not only promote the use of environmentally friendly surfactants but also contribute to sustainable waste management and reduce dependence on non-renewable resources. This study explores the efficient use of wastes and other low-cost substrates to produce glycolipids BS, identifies efficient substrates for commercial production, and recommends strategies to improve productivity and use BS in environmental remediation.

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches.

Ferroptosis, a unique form of programmed cell death, is initiated by an excess of iron accumulation and lipid peroxidation-induced damage. There is a growing body of evidence indicating that ferroptosis plays a critical role in the advancement of tumors. The increased metabolic activity and higher iron levels in tumor cells make them particularly vulnerable to ferroptosis. As a result, the targeted induction of ferroptosis is becoming an increasingly promising approach for cancer treatment. This review offers an overview of the regulatory mechanisms of ferroptosis, delves into the mechanism of action of traditional small molecule ferroptosis inducers and their effects on various tumors. In addition, the latest progress in inducing ferroptosis using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic therapy (SDT) and nanomaterials is summarized. Finally, this review discusses the challenges and opportunities in the development of ferroptosis-inducing agents, focusing on discovering new targets, improving selectivity, and reducing toxic and side effects.

Xenon Antiaggregant Effects.

In in vitro model of short-term therapeutic inhalation of Xe/O2 mixture, xenon in millimolar concentrations led to a pronounced decrease in induced platelet aggregation in the platelet-enriched blood plasma. The maximum and statistically significant decrease occurred in response to induction by collagen (by ≈30%, p≤0.01) and ADP (by ≈25%, p≤0.01). A slightly weaker but statistically significant reduction in aggregation appeared in response to ristocetin (by ≈12%, p≤0.01) and epinephrine (by ≈9%, p≤0.01). It should be noted that the spontaneous aggregation exceeded the reference values in the control group. Nevertheless, even at minimal absolute values, spontaneous platelet aggregation decreased by 2 times in response to xenon (p≤0.01). The reasons for the decrease of spontaneous and induced aggregation are xenon accumulation in the lipid bilayer of the membrane with subsequent nonspecific (mechanical) disassociation of membrane platelet structures and specific block of its distinct from neuronal NMDA receptor.

Lipid-derived electrophiles inhibit the function of membrane channels during ferroptosis.

The therapeutic targeting of ferroptosis requires full understanding of the molecular mechanism of this regulated cell death pathway. While lipid-derived electrophiles (LDEs), including 4-hydroxy-2-nonenal (4-HNE), are important biomarkers of ferroptosis, a functional role for these highly reactive species in ferroptotic cell death execution has not been established. Here, through mechanistic characterization of LDE-detoxification impairment, we demonstrate that LDEs mediate altered protein function during ferroptosis. Applying live cell fluorescence imaging, we first identified that export of glutathione-LDE-adducts through multidrug resistance-associated protein (MRP) channels is inhibited following exposure to a panel of ferroptosis inducers (FINs) with different modes of action (type I-IV FINs erastin, RSL3, FIN56, and FINO2). This channel inhibition was recreated by both initiation of lipid peroxidation and treatment with 4-HNE. Importantly, treatment with radical-trapping antioxidants prevented impaired LDE-adduct export when working with both FINs and lipid peroxidation initiators but not 4-HNE, pinpointing LDEs as the cause of this inhibited MRP activity observed during ferroptosis. Our findings, when combined with reports of widespread LDE alkylation of key proteins following ferroptosis induction, including MRP1, set a precedent for LDEs as critical mediators of ferroptotic cell damage. Lipid hydroperoxide breakdown to form truncated phospholipids and LDEs may fully explain membrane permeabilization and modified protein function downstream of lipid peroxidation, offering a unified explanation of the molecular cell death mechanism of ferroptosis.

Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot.

Immunotherapy has emerged as a promising cancer treatment option in recent years. In immune "hot" tumors, characterized by abundant immune cell infiltration, immunotherapy can improve patients' prognosis by activating the function of immune cells. By contrast, immune "cold" tumors are often less sensitive to immunotherapy owing to low immunogenicity of tumor cells, an immune inhibitory tumor microenvironment, and a series of immune-escape mechanisms. Immunogenic cell death (ICD) is a promising cellular process to facilitate the transformation of immune "cold" tumors to immune "hot" tumors by eliciting innate and adaptive immune responses through the release of (or exposure to) damage-related molecular patterns. Accumulating evidence suggests that various traditional therapies can induce ICD, including chemotherapy, targeted therapy, radiotherapy, and photodynamic therapy. In this review, we summarize the biological mechanisms and hallmarks of ICD and introduce some newly discovered and technologically innovative inducers that activate the immune system at the molecular level. Furthermore, we also discuss the clinical applications of combing ICD inducers with cancer immunotherapy. This review will provide valuable insights into the future development of ICD-related combination therapeutics and potential management for "cold" tumors.

Oridonin, a small molecule inhibitor of cancer stem cell with potent cytotoxicity and differentiation potential.

Cancer stem cells (CSCs) drive malignant tumor progression, recurrence, and metastasis with unique characteristics, including self-renewal and resistance to conventional treatments. Conventional differentiation inducers, although promising, have limited cytotoxicity and may inadvertently enhance CSC stemness. To address these challenges, ongoing efforts are dedicated to developing strategies that can effectively combine both cytotoxicity and differentiation-inducing effects. In this study, we introduce oridonin (Ori), a small molecule with dual differentiation-inducing and cytotoxicity properties capable of eliminating tumor CSCs. We isolated CSCs in B16F10 cells using the Hoechst side population method and assessed the differentiation effect of Ori. Ori's differentiation-inducing effect was further evaluated using human acute promyelocytic leukemia. The cytotoxic potential of Ori against MCF-7 and B16F10 cell lines was assessed through various methods. In vivo anti-tumor and anti-CSC efficacy of Ori was investigated using mouse melanoma and CSCs melanoma models. Safety evaluation included zebrafish embryotoxicity and mouse acute toxicity experiments. As a result, Ori effectively dismantles tumorspheres, inhibits proliferation, and reduces the expression of CSC-specific markers. It induces significant differentiation, especially in the case of NB4. Additionally, Ori upregulates TP53 expression, mitigates the hypoxic tumor microenvironment, suppresses stemness, and inhibits PD-L1 expression, prompting a robust anti-cancer immune response. Ori demonstrates pronounced cytotoxicity, inducing notable pro-apoptotic effects on B16F10 and MCF-7 cells, with specific triggering of mitochondrial apoptosis. Importantly, Ori maintains a commendable biosafety record. The dual-action prowess of Ori not only induces the differentiation of CSCs but also dispatches differentiated and residual tumor cells, effectively thwarting the relentless march of tumor progression.

Ferroptosis: Iron-mediated cell death linked to disease pathogenesis.

Ferroptosis is an iron-mediated regulatory cell death pattern characterized by oxidative damage. The molecular regulating mechanisms are related to iron metabolism, lipid peroxidation, and glutathione metabolism. Additionally, some immunological signaling pathways, such as the cyclic GMP-AMP synthase-stimulator ofinterferon genes axis, Janus kinase-signal transducer and activator of transcription 1 axis, and transforming growth factor beta 1-Smad3 axis may also participate in the regulation of ferroptosis. Studies have shown that ferroptosis is closely related to many diseases such as cancer, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases. Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases, the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of the aforementioned conditions.

Targeting ferroptosis for leukemia therapy: exploring novel strategies from its mechanisms and role in leukemia based on nanotechnology.

The latest findings in iron metabolism and the newly uncovered process of ferroptosis have paved the way for new potential strategies in anti-leukemia treatments. In the current project, we reviewed and summarized the current role of nanomedicine in the treatment and diagnosis of leukemia through a comparison made between traditional approaches applied in the treatment and diagnosis of leukemia via the existing investigations about the ferroptosis molecular mechanisms involved in various anti-tumor treatments. The application of nanotechnology and other novel technologies may provide a new direction in ferroptosis-driven leukemia therapies. The article explores the potential of targeting ferroptosis, a new form of regulated cell death, as a new therapeutic strategy for leukemia. It discusses the mechanisms of ferroptosis and its role in leukemia and how nanotechnology can enhance the delivery and efficacy of ferroptosis-inducing agents. The article not only highlights the promise of ferroptosis-targeted therapies and nanotechnology in revolutionizing leukemia treatment, but also calls for further research to overcome challenges and fully realize the clinical potential of this innovative approach. Finally, it discusses the challenges and opportunities in clinical applications of ferroptosis.

Nanoparticles and Chemical Inducers: A Sustainable Shield against Onion White Rot.

This study investigated the effectiveness of nanoparticles and chemical inducers in managing onion white rot caused by Sclerotium cepivorum. The pathogen severely threatens onion cultivation, resulting in significant yield losses and economic setbacks. Traditional fungicides, though effective, raise environmental concerns, prompting a shift toward eco-friendly alternatives. In this study, four S. cepivorum isolates were utilized, each exhibiting varying degrees of pathogenicity, with the third isolate from Abu-Hamad demonstrating the highest potency. During the in vitro studies, three nanoparticles (NPs) were investigated, including Fe3O4 NPs, Cu NPs, and ZnO NPs, which demonstrated the potential to inhibit mycelial growth, with salicylic acid and Fe3O4 NPs exhibiting synergistic effects. In vivo, these nanoparticles reduced the disease incidence and severity, with Fe3O4 NPs at 1000-1400 ppm resulting in 65.0-80.0% incidence and 80.0-90.0% severity. ZnO NPs had the most positive impact on the chlorophyll content, while Cu NPs had minimal effects. At 1000 ppm, Fe3O4 NPs had variable effects on the phenolic compounds (total: 6.28, free: 4.81, related: 2.59), while ZnO NPs caused minor fluctuations (total: 3.60, free: 1.82, related: 1.73). For the chemical inducers, salicylic acid reduced the disease (10.0% incidence, 25.0% to 10.0% severity) and promoted growth, and it elevated the chlorophyll values and enhanced the phenolic compounds in infected onions. Potassium phosphate dibasic (PDP) had mixed effects, and ascorbic acid showed limited efficacy toward disease reduction. However, PDP at 1400 ppm and ascorbic acid at 1000 ppm elevated the chlorophyll values and enhanced the phenolic compounds. Furthermore, this study extended to traditional fungicides, highlighting their inhibitory effects on S. cepivorum. This research provides a comprehensive comparative analysis of these approaches, emphasizing their potential in eco-friendly onion white rot management.

Biochemical and Molecular Basis of Chemically Induced Defense Activation in Maize against Banded Leaf and Sheath Blight Disease.

Maize is the third most vital global cereal, playing a key role in the world economy and plant genetics research. Despite its leadership in production, maize faces a severe threat from banded leaf and sheath blight, necessitating the urgent development of eco-friendly management strategies. This study aimed to understand the resistance mechanisms against banded leaf and sheath blight (BLSB) in maize hybrid "Vivek QPM-9". Seven fungicides at recommended doses (1000 and 500 ppm) and two plant defense inducers, salicylic acid (SA) and jasmonic acid (JA) at concentrations of 50 and 100 ppm, were applied. Fungicides, notably Azoxystrobin and Trifloxystrobin + Tebuconazole, demonstrated superior efficacy against BLSB, while Pencycuron showed limited effectiveness. Field-sprayed Azoxystrobin exhibited the lowest BLSB infection, correlating with heightened antioxidant enzyme activity (SOD, CAT, POX, ß-1,3-glucanase, PPO, PAL), similar to the Validamycin-treated plants. The expression of defense-related genes after seed priming with SA and JA was assessed via qRT-PCR. Lower SA concentrations down-regulated SOD, PPO, and APX genes but up-regulated CAT and ß-1,3-glucanase genes. JA at lower doses up-regulated CAT and APX genes, while higher doses up-regulated PPO and ß-1,3-glucanase genes; SOD gene expression was suppressed at both JA doses. This investigation elucidates the effectiveness of certain fungicides and plant defense inducers in mitigating BLSB in maize hybrids and sheds light on the intricate gene expression mechanisms governing defense responses against this pathogen.