Microplastics have emerged as widespread terrestrial contaminants, yet their mechanistic effects on medicinal plants remain largely unresolved. Here, we investigated the uptake, intracellular movement, and multi-level stress responses of Tetrastigma hemsleyanum, a flavonoid-rich medicinal species, under exposure to polystyrene microplastics. Confocal imaging confirmed extensive microplastic accumulation in the roots and vascular transport to the leaves. Microplastic stress induced pronounced oxidative damage, as evidenced by a 45.2 percent increase in malondialdehyde, enhanced peroxidase and catalase activities, and a 42.5 percent reduction in total chlorophyll content and photosynthetic efficiency. Multi-omics integration revealed coordinated suppression of photosynthetic energy metabolism, exemplified by the strong repression of RPN2A, along with pronounced activation of PER31 and key genes of the flavonoid biosynthetic pathway. These transcriptional shifts corresponded with elevated accumulation of antioxidant metabolites, including catechin, dihydrokaempferol, and quercetin. Collectively, this study supports a mechanistic model in which microplastics disrupt redox homeostasis and constrain ATP supply, initiating a whole plant reallocation of metabolic resources from carbon fixation toward flavonoid-centered antioxidant defense. This adaptive shift provides insight into plant resilience to emerging pollutants and highlights the potential vulnerability of medicinal quality under microplastic contamination.

Precise control of pre-mRNA splicing is vital for transcriptome integrity, and its disruption is an emerging cancer vulnerability. Here, we use indisulam to degrade RBM39 and show that the clinical ALK inhibitor alectinib can be repurposed to inhibit SRPK1. Co-treatment of indisulam and alectinib inhibited cell proliferation, induced apoptosis, and caused cell-cycle arrest in multiple cancer cell lines, including MYCN-amplified high-risk neuroblastoma. RNA sequencing revealed enhanced splicing defects preferentially in DNA repair-related genes following combination treatment, leading to R-loop accumulation and increased DNA damage. In the Th-MYCN/ALKF1174L neuroblastoma mouse model, combination therapy induced complete tumor regression and significantly improved survival rates compared with monotherapies. These findings demonstrate that combining indisulam and alectinib is a promising approach to treating aggressive malignancies such as high-risk neuroblastoma, exploiting the untapped polypharmacology of alectinib as an RNA splicing inhibitor and supporting the therapeutic value of co-targeting interdependent splicing factors for synergistic benefit.

Solanum lycopersicum SlMYB2 enhances drought, salt, and cadmium stress tolerance by upregulating stress-responsive genes, improving proline levels and antioxidant activity, and reducing oxidative damage. MYB transcription factors are widely present in plants and play critical roles in regulating responses to abiotic stresses, yet most remain poorly characterized. In this study, a typical R2R3-MYB gene (SlMYB2) from Solanum lycopersicum was isolated and identified, and its role in abiotic stress response was investigated. Stress-related cis-acting elements were present in the promoter sequence of SlMYB2, such as drought response elements, low-temperature response elements, and ABA response elements. Subcellular localization analysis showed that SlMYB2 is localized in the nucleus. Transactivation activity assay in yeast cells revealed that SlMYB2 has transactivation activity, and its active domain is located in the C-terminal. Drought, salt, and cadmium stress resulted in a rapid induction of SlMYB2 expression in tomato. Furthermore, compared to wild-type plants, SlMYB2-overexpressing Arabidopsis thaliana showed a higher seed germination rate and cotyledon greening rate, along with significantly increased proline content, chlorophyll levels, and peroxidase activity under drought, salt, and cadmium stress. In contrast, the transgenic lines exhibited a significantly lower malondialdehyde content than the wild-type. Expression analysis demonstrated that SlMYB2 overexpression upregulated key drought-, salt-, and cadmium-responsive genes under stress conditions, supporting its central role in the transcriptional regulation of integrated multi-stress tolerance in plants. These results indicated that SlMYB2 acts as a positive regulator in enhancing plant tolerance to drought, salt, and cadmium stress.

GABA enhanced Al tolerance in broad bean through reducing Al accumulation by fine-tuning transport genes, reinforcing transcriptional activation of lignin biosynthesis, and enhancing internal detoxification by reconfiguring (iso)flavonoid biosynthesis. Aluminum (Al) toxicity is recognized as the second largest abiotic factor that limits crop productivity worldwide. While γ-aminobutyric acid (GABA) is known to enhance plant stress tolerance, its role in Al resistance, particularly in legumes like broad bean (Vicia faba L.), remains poorly understood at the molecular level. This study integrated physiological and transcriptomic analyses to elucidate the mechanisms by which exogenous GABA alleviates Al toxicity in broad bean. Results showed that 1000 μM GABA significantly mitigated Al-induced root growth inhibition. Crucially, GABA reduced root and shoot Al concentrations by 52.0% and 55.2%, respectively, which was linked to the upregulation of VfALMT1 (mediating Al efflux) and downregulation of VfNIP1;2 (mediating Al root-to-shoot translocation). Concurrently, GABA alleviated the Al-induced suppression of lignin biosynthesis, reinforcing the cell wall as a physical barrier. Furthermore, GABA synergistically amplified the flavonoid biosynthesis pathway and uniquely activated the Al-suppressed isoflavonoid biosynthesis pathway, enhancing antioxidant capacity and potentially internal detoxification. These findings demonstrate that GABA enhances Al tolerance not by simply reversing Al-induced changes but by actively reprogramming key processes, including Al transport, cell wall fortification, and secondary metabolism. This study provides novel insights into GABA's multifaceted role as a signaling molecule in plant Al stress tolerance, offering potential strategies for improving crop resilience in acid soils.

Breast cancer remains one of the leading causes of cancer-related mortality in women worldwide. Breast cancer stem cells (BCSCs) contribute to tumor initiation, metastasis, recurrence, and resistance to therapy. The Wnt signaling pathway is a major regulator of stemness properties and is associated with poor clinical outcomes. BIBR1532 is a selective telomerase inhibitor widely used in cancer research due to its ability to inhibit telomerase activity in tumor cells with minimal toxicity in normal tissues. This study aimed to investigate the effects of BIBR1532 on the Wnt signaling pathway in breast cancer cells and BCSCs.

Dysregulation of YAP, the terminal effector of the Hippo pathway, contributes to cancer progression and drug resistance. Its role in glioblastoma (GBM), the most aggressive brain cancer, remains incompletely understood. Single-cell RNA sequencing data from a published GBM dataset were reanalyzed to assess YAP expression across cell populations. YAP was silenced via shRNA in GBM cell lines (U-251 MG, U-87 MG) and patient-derived GBM cells. Resveratrol (RV), a natural blood-brain barrier-permeable compound, was evaluated for growth inhibition and YAP-targeted effects. Functional assays measured proliferation, spheroid formation, migration, invasion, and drug sensitivity. YAP and its cofactor TEAD were highly upregulated in GBM cells compared with normal brain and stromal cells. YAP depletion by shRNA suppressed proliferation, spheroid formation, migration, and invasion. RV treatment similarly inhibited YAP expression, reducing proliferation and viability in monolayer and 3D spheroid cultures, and impairing migration and invasion via epithelial-mesenchymal transition (EMT) inhibition. RV-mediated YAP suppression also enhanced sensitivity to temozolomide (TMZ) and carmustine (BCNU), increasing their cytotoxicity in GBM cells. RV acts as a novel YAP inhibitor in GBM, impairing malignant phenotypes and potentiating the effects of standard chemotherapy. These findings support RV as a potential adjunct in YAP-targeted GBM therapy, warranting further in vivo validation for clinical translation.

We hypothesized that B-GATA family transcription factors have important roles in growth regulation in moss. We analyzed B-GATA family transcription factor mutants from Physcomitrium patens and Arabidopsis thaliana to assess growth, gene expression, and cytokinin-related processes under varying nitrogen conditions. We found that nitrogen-dependent growth and transcriptional regulation are strongly impaired in mutants from Physcomitrium and Arabidopsis. We detected altered cytokinin homeostasis or signaling in the mutants, linking hormonal imbalance to growth and transcription defects. We demonstrated a conserved, critical role of B-GATAs in plant nitrogen-responsive growth. Results suggest that B-GATAs influence nitrogen-regulated transcription downstream from cytokinin, supporting an ancient, evolutionarily conserved mechanism connecting nutrient signaling to growth. We provided experimental evidence for the long-speculated but as-yet not demonstrated role of GATA transcription factors in nitrogen-dependent growth in land plants.

Mitochondrial dysfunction represents a central hallmark of aging and a broad spectrum of chronic diseases, ranging from metabolic to neurodegenerative and ocular disorders. Nicotinamide riboside (NR), a vitamin B3 derivative and efficient precursor of NAD+ (nicotinamide adenine dinucleotide), and berberine (BBR), an isoquinoline alkaloid widely investigated in metabolic regulation, have independently emerged as promising mitochondrial modulators. NR enhances cellular NAD+ pools, thereby activating sirtuin-dependent pathways, stimulating PGC-1α-mediated mitochondrial biogenesis, and triggering the mitochondrial unfolded protein response (UPRmt). BBR, by contrast, primarily activates AMPK (AMP-activated protein kinase) and interacts with respiratory complex I, improving bioenergetics, reducing mitochondrial reactive oxygen species, and promoting mitophagy and organelle quality control. Importantly, despite distinct upstream mechanisms, NR and BBR converge on shared signaling pathways that support mitochondrial health, including redox balance, metabolic flexibility, and immunometabolic regulation. Unlike previous reviews addressing these compounds separately, this article integrates current preclinical and clinical findings to provide a unified perspective on their converging actions. We critically discuss translational opportunities as well as limitations, including heterogeneous clinical outcomes and the need for robust biomarkers of mitochondrial function. By outlining overlapping and complementary mechanisms, we highlight NR and BBR as rational combinatorial strategies to restore mitochondrial resilience. This integrative perspective may guide the design of next-generation clinical trials and advance precision approaches in mitochondrial medicine.

Weed stress remains a major limiting factor in cotton production, and glyphosate-tolerant varieties provide an effective solution for chemical weed control. However, achieving a balance between herbicide tolerance and agronomic physiological traits remains challenging. In this study, three hybrid combinations were generated by crossing a glyphosate-tolerant cotton line (GGK2) with conventional elite lines and were comprehensively evaluated. Gene expression analysis revealed that the classical detoxification gene GAT was significantly downregulated in all hybrid combinations, whereas the expression of GR79-EPSPS, a gene associated with glutathione metabolism and oxidative stress response, was markedly elevated, particularly in the GGK2 × Y4 combination. This differential expression pattern suggests that GR79-EPSPS may compensate for the reduced function of GAT by conferring oxidative protection under herbicide stress. Physiological determination indicated that hybrid combinations with enhanced GR79-EPSPS expression, especially GGK2 × Y5, exhibited superior photosynthetic pigment composition and photosystem II (PSII) efficiency, validating the role of GR79-EPSPS in maintaining photosynthetic stability. Agronomic trait assessment demonstrated that GGK2 × Y4 achieved significant biomass accumulation and yield improvement through heterosis, although fiber quality improvement was limited. This study effectively enhanced the herbicide resistance of conventional cotton through crossbreeding and revealed that the interaction between GR79-EPSPS and GAT can improve cotton tolerance to herbicides, thereby providing a breeding strategy for developing cotton varieties with both herbicide tolerance and superior agronomic traits.

One significant trend in the research of plant treatment methods is that regarding the use of natural-based methods in plant protection. In this study, antimicrobial activity and changes in MdPR10 gene expression were tested for a total of five plant pathogens in a model of apple fruits, where strawberry and ivy EOs were used. The vapor-phase chemical composition of both EOs was profiled using HS-GC-MS. qRT-PCR was applied for a bacterial response analysis, together with disk diffusion assays, and minimum inhibitory concentrations were determined. To elucidate the molecular basis of the antibacterial potential of essential oils (EOs), docking analyses were performed. For Xanthomonas arboricola and Pectobacterium carotovorum, the presence of EOs resulted in the downregulation of MdPR10. Strawberry EO was more effective against weakly virulent strains of bacteria; ivy EO had greater inhibitory effects. HS-GC-MS detected 13 volatiles in strawberry EO-dominated by ethyl butyrate, ethyl 2-methylbutanoate, ethyl hexanoate, and ethyl 3-methylbutanoate-and 16 in ivy EO, characterized by monoterpenes and monoterpenoids with 1,8-cineole as the principal component. P-cymene showed the most potent binding activity against D-alanine-D-alanine ligase. Ivy EO has the potential to be effective as a natural preservative alternative mainly in postharvest technology.

Curcuminoids demonstrate diverse pharmacological activity as antioxidant, neuroprotective, antitumor, and anti-inflammatory drugs. Dimethoxycurcumin (DMC) is a metabolically stable analog of curcumin, and both drugs modify the activity of several epigenetic enzymes that affect DNA methylation and histone modifications. 5-hydroxymethylcytosine (5hmC) is an epigenetic mark involved in active demethylation and in gene expression regulation. The effect of curcuminoids on the activity and expression of TET enzymes involved in 5hmC oxidation and active demethylation in leukemia cells is unclear. In this study, we investigated the impact of curcumin and DMC on the activity and expression of the three isoforms of TET enzymes. We also studied their effect on global 5hmC and performed a genome-wide analysis of 5hmC distribution at the single CpG level using oxidative bisulfite sequencing, which can differentiate between 5hmC and 5-methylcytosine. Both curcumin and DMC increased the activity and the mRNA expression of the three isoforms of TET. Concordantly, they also increased the global 5hmC level in leukemia cells. Single CpG analysis showed that both drugs induced a 5hmC increase and active demethylation at gene promoters, CpG islands and shores, exons, introns, and intergenic regions. Curcumin induced a promoter 5hmC increase in 194 genes and promoter-active demethylation in 154 genes. On the other hand, DMC induced a promoter 5hmC increase in 173 genes and promoter-active demethylation in 171 genes. Our study identifies curcuminoids as active demethylators through the activation of TET enzymes and provides a rationale for testing their combination with DNA hypomethylating agents in leukemia animal models.

The impairment of neural crest cells (NCCs) plays a pivotal role in the pathogenesis of fetal alcohol spectrum disorders (FASD). Epigenetic regulators mediate ethanol-induced disruptions in NCC development and represent promising targets for nutritional interventions. Here, we developed a biologically informed machine learning framework to predict nutritional supplements that modulate five key epigenetic regulators (miR-34a, DNMT3a, HDAC, miR-125b, and miR-135a) and mitigate ethanol's adverse effects on NCCs. The optimized models demonstrated robust predictive performance and identified a number of nutritional supplements that could attenuate ethanol-induced NCC impairment, including resveratrol, vitamin B12, emodin, quercetin, and broccoli sprout-derived compounds. Our optimized models also revealed structural features that are critical for mitigating ethanol-induced NCC impairment through specific epigenetic mechanisms. These findings support predictive modeling as a tool to prioritize nutritional supplements for further investigation and the development of dietary strategies to prevent or reduce the risk of FASD.

Diabetes mellitus (DM) leads to renal damage through oxidative stress. Carvacrol (CAR), a monoterpenoid phenol, possesses anti-inflammatory and antioxidant properties. We investigated the potential effects of CAR on histological, gene expression, and biochemical parameters in a rat model of DM. Four groups were created: group 1, control; group 2 (n = 9), DM; group 3 (n = 9), DM + dimethyl sulfoxide (DMSO); and group 4 (n = 9), DM + CAR. DM was created by injecting streptozotocin (STZ). CAR (20 mg/kg) was prepared through dissolution in 0.1% DMSO. CAR and 0.1% DMSO were administered daily for 4 weeks to groups 4 and 3, respectively. At the end of this study, urea, creatinine, paraoxonase-1 (PON-1), and arylesterase (ARES) were measured in serum samples. Histopathological changes and expression of Nuclear factor erythroid 2-related factor 2 (Nrf-2) in renal tissues were assessed. Immunohistochemical(ihc) staining and RT-qPCR analysis were performed to evaluate apoptosis, focusing on Bax and Bcl-2gene expression. Masson's trichrome(MT) staining and RT-qPCR analysis of COL1A1 and COL3A1 mRNA levels were used to assess fibrosis. Increased urea and creatinine levels in DM were significantly decreased after CAR administration. CAR application also improved reduced levels of PON 1 and ARES, which are associated with diabetes. Both immunohistochemistry and RT-qPCR analyses revealed that CAR therapy mitigated the diabetes-induced elevation in Bax and reduction in Bcl-2 expression. CAR treatment improved histopathological findings and renal Nrf-2 immunofluorescence(if) intensity. Furthermore, gene expression analysis demonstrated that COL1A1 and COL3A1 were upregulated in DM, while CAR administration downregulated them. In conclusion, CAR has a protective role in decreasing renal impairment linked to DM by regulating Bax and Bcl-2 levels and rectifying histological damage.

With an aging population and the increase in life expectancy, colorectal cancer is becoming increasingly common. Currently, the mainstay of treatment is chemotherapy, which can cause a variety of side effects. However, herbalists in many cultures have long used herbs to promote health and treat various diseases, including colon cancer. This study investigated the chemical components of shell extracts from Plukenetia volubilis (sacha inchi) and their effects on colon cancer cells. First, cytotoxicity against both normal and cancer cells was assessed, followed by cell migration and invasion. Finally, transcriptomic and proteomic analyses were performed to investigate molecular mechanisms. Phytochemical analysis showed a total phenolic content of 134.61 ± 0.27 mgGAE/g extract and a total flavonoid content of 5.75 ± 0.01 mgQE/g extract; moreover, lidocaine (10.57%) and linolenic acid (10.39%) were identified as the most abundant compounds. In vitro, the extract inhibited cell migration, invasion, and colony formation and was associated with potential modulations of the Hippo pathways and epithelial-mesenchymal transition. Therefore, it can be concluded that these extracts are effective in inhibiting the progression of colon cancer cells, and thus, they can prospectively be developed as a dietary supplement or therapeutic agent for the treatment of colon cancer in the future.

Cadmium (Cd) induces oxidative stress and disrupts nuclear organization and chromatin-associated metabolic processes in plant cells. Therefore, identifying natural, biodegradable, non-bioaccumulative compounds that enhance plant tolerance to heavy metals is crucial. We hypothesized that Cd exposure (175 µM CdCl2, 24 h) activates mitogen-activated protein kinases (MAPKs), triggering defined epigenetic modifications that lead to transcriptional repression, and that thyme oil (TO; 0.03% (v/v), emulsified) mitigates these effects by stabilizing chromatin organization. We analyzed nuclear MAPK (p44/42) activation, global DNA methylation (5-methylcytosine; 5-mC), and selected histone modifications as key components of early stress signaling and epigenetic regulation. We found that Cd exposure doubled global 5-mC levels and caused pronounced alterations in histone marks, including decreases in H3K4Me2 (~34%), H3T45Ph (~48%), and H4K5Ac, accompanied by strong increases in H3K9Ac (~57%) and H3K56Ac (~148%). These changes were associated with chromatin condensation and reduced transcriptional activity. In contrast, co-treatment with TO maintained MAPK activity and epigenetic parameters close to control levels, preventing chromatin compaction and transcriptional repression. Together, these findings indicate that TO stabilizes the nuclear signaling-epigenetic interface under Cd stress and represents a promising bioprotective strategy. This work provides the first demonstration that TO modulates both MAPK activation and Cd-induced histone modifications in plants.

Seed germination and early growth in rice are critical stages influenced by the hormonal balance between gibberellins (GA) and abscisic acid (ABA), particularly under low-temperature stress. This study investigated the effects of GA3 and ABA on seed germination, embryonic growth, gene expression, and biochemical activities in rice cultivars with contrasting tolerance to low temperatures. GA3 markedly improved germination in resistant cultivars Nagdong and CNDH77, whereas susceptible cultivars showed minimal improvement, while ABA strongly inhibited germination, especially under higher concentrations. GA3 also promoted embryonic growth, with resistant cultivars displaying the longest embryo cells (10.10 µm and 13.49 µm, respectively), whereas ABA suppressed embryonic growth and completely inhibited germination in susceptible cultivars. Upregulation of GA biosynthesis (OsCPS1 and OsKS1) and signaling genes (OsGID1 and OsGID2) in resistant cultivars correlated with enhanced germination and growth, whereas ABA-induced ABI5 expression suppressed germination, particularly in susceptible cultivars. Hormone quantification confirmed increased endogenous GA3 after GA3 treatment and reduced ABA levels under ABA treatment. Additionally, GA3 modulated ABA signaling genes, upregulating OSK3, ABI3, ABI4, and ABI5, while ABA treatment had contrasting effects, particularly between resistant and susceptible cultivars. GA3 treatment also enhanced the expression of GA biosynthesis and signaling genes (OsCPS1, OsKS1, OsGID1, and OsGID2), whereas ABA treatment upregulated ABA catabolic genes (OsABA8ox2). GA3 also enhanced amylase activity and sugar-related gene expression, supporting its role in energy mobilization during germination. Conversely, ABA suppressed cell elongation, reducing it to 4.45 µm in CNDH77 under 100 µM ABA. These findings provide valuable insights into the hormonal regulation of rice seed germination and growth under low-temperature stress, offering potential strategies to enhance seed vigor and stress tolerance in rice breeding.

The therapeutic potential of functional nutrients has garnered considerable attention for enhancing resilience signaling and counteracting the damage to human health caused by microplastic pollutants. The intricate interactions between microplastics (MPs) and nanoplastics (NPs) and functional nutrients, including polyphenols, flavonoids, phenylpropanoids, phenolic acids, diterpenoids, and triterpenoids, have been shown to improve blood-brain barrier (BBB) homeostasis and brain function by inhibiting oxidative stress, ferroptosis, and inflammation linked to the pathogenesis of metabolic and brain disorders. Interestingly, nutrients exhibit biphasic dose-response effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and stress-resilience proteins at minimum doses, thereby preventing or blocking MP and NP-induced damage. Notably, chronic exposure to environmental pollutants causes aberrant regulation of NFE2L2 gene and related antioxidant signaling, which can exacerbate selective susceptibility to brain insulin resistance under inflammatory conditions. This, in turn, impairs glucose metabolism and facilitates β-amyloid (Aβ) plaque synthesis leading to the onset and progression of Alzheimer's disease (AD), also known as "Type 3 diabetes". This pathological process triggered by oxidative stress, inflammation, and ferroptosis creates a vicious cycle that ultimately contributes to neuronal damage and loss. The review aims to investigate the therapeutic potential of functional nutrients targeting the Nrf2 pathway and stress resilience proteins to regulate epigenetic alterations, and to explore the underlying molecular mechanisms using innovative in vitro platforms for the development of promising preventive strategies and personalized nutritional interventions to attenuate oxidative stress, ferroptosis, and inflammation, with the goal of ultimately improving clinical outcomes.

Peroxisome proliferator-activated receptor γ (PPARγ) plays a crucial role in the differentiation and maturation of preadipocytes. PPARγ promotes adipogenesis by inducing the expression of fatty acid-binding protein 4 (FABP4). Uncoupling protein 1 (UCP1) is involved in non-shivering thermogenesis and adipocyte browning. The present study aimed to examine the effects of luteolin and apigenin on the gene expression levels and protein concentrations of PPARγ and FABP4, which are involved in adipogenesis, and their effect on UCP1, a thermogenic protein, in the 3T3-L1 preadipocyte cell line. Luteolin and apigenin were prepared at concentrations of 10, 20, and 40 µM and applied to 3T3-L1 preadipocytes during differentiation and maturation. Gene expression levels were measured by real-time PCR, and protein concentrations were measured by ELISA. It was found that the doses used did not cause cytotoxicity in the cells. Luteolin treatment during differentiation and maturation resulted in a decrease in PPARγ and FABP4 gene expression, although the protein concentrations remained unchanged. Additionally, while luteolin treatment did not significantly alter UCP1 gene expression or protein levels during differentiation, it led to a decrease in UCP1 protein concentration during maturation. Apigenin treatment also tended to decrease PPARγ and FABP4 gene expression compared to the control, although no statistical difference was observed. These results suggest that luteolin and apigenin may have regulatory effects on adipogenesis by modulating PPARγ, FABP4, and UCP1 gene expression.

Triple Negative Breast Cancers (TNBCs) are heterogeneous and aggressive tumors with a median overall survival of less than two years. Despite the availability of new drugs, the prognosis remains poor, implicating a more aggressive clinical course in the metastatic setting. This study investigated the effects of metronomic treatment (mCHT) with 5-fluorouracil (5-FU) plus vinorelbine (VNR) on spheroids derived from two different TNBC cell lines (BT-549 and MDA-MB-231) and a patient-derived primary cell line (MS-186). mCHT significantly reduced spheroid growth and altered spheroid architecture, with a pronounced effect in second-generation spheroids, enriched in self-renewing cancer stem cells (CSCs). Expression of CSC-related markers (CD44, CD133, NOTCH-1, and MYC) was more significantly altered-both at the mRNA and protein levels-by mCHT than by standard treatment (STD). In MS-186-derived spheroids, mCHT downregulated EZH2 and STAT3, key regulators of CSC maintenance, and reduced H3K27ac, suggesting a global epigenetic reprogramming. Unlike STD, which partially and transiently reduced stemness markers, mCHT achieved sustained suppression, indicating preferential targeting of therapy-resistant CSCs. These results indicate mCHT as a promising strategy for specifically aiming at the CSC-like compartment in TNBC, underscoring a therapeutic approach that reprograms key epigenetic networks and overcomes resistance to treatment.

Lung cancer (LC) remains the leading cause of cancer-related death in the United States despite advances in therapy. Growth hormone (GH) action has been implicated in tumor progression and therapy resistance across multiple cancers, but its role in LC, particularly non-small cell lung cancer (NSCLC), remains poorly defined. In cancer cells, GH promotes chemoresistance through upregulation of drug-efflux pumps, induction of epithelial-to-mesenchymal transition (EMT), and inhibition of apoptosis. Notably, GH receptor (GHR) expression is significantly elevated in NSCLC compared to normal lung tissue, suggesting a potential therapeutic opportunity. In this study, we investigated the impact of GH action on therapy resistance and tumor progression using integrated transcriptomic analyses and in vitro experiments. Analyses of transcriptomic data from NSCLC patients revealed that high tumoral GHR expression correlates with reduced overall survival, and with upregulation of genes involved in distinct therapy refractory pathways. Our in vitro studies demonstrated that GH promotes chemoresistance in NSCLC cell lines through activation of ABC transporters and EMT pathways, whereas GHR antagonism with the GH receptor antagonist, pegvisomant, effectively counteracts these effects and improves chemotherapy efficacy significantly. Together, our findings identify GHR signaling as a contributor to aggressive and therapy-resistant phenotypes in NSCLC in vitro and suggest that GHR antagonism may enhance chemotherapy sensitivity. These results provide a rationale for further in vivo and mechanistic studies to evaluate the therapeutic potential of targeting GHR in NSCLC.