Although androgen receptor (AR) inhibitors such as enzalutamide are initially effective in castration resistant prostate cancer through suppression of AR signaling pathway, acquired resistance invariably develops, presenting a significant therapeutic challenge. Understanding the mechanisms of enzalutamide resistance (ENZR) is essential for developing improved therapeutic strategies. Here, we demonstrated that ZNF711 was significantly overexpressed in ENZR, and high ZNF711 levels correlated with poor clinical outcomes. Functionally, ZNF711 promoted ENZR progression both in vitro and in vivo. Mechanistically, ZNF711 directly bound to the AR promoter, transcriptionally upregulating AR expression. ZNF711 knockdown markedly reduced AR chromatin occupancy at target loci. Additionally, ZNF711 formed a complex with BMI1 and AR, enhancing AR signaling pathway by suppressing CpG methylation at the promoter of AR and its downstream target genes (e.g., KLK3, TMPRSS2), thereby potentiating AR transcriptional activity. Notably, targeting ZNF711 with antagonistic chimeric siRNA restored enzalutamide sensitivity in vivo. Collectively, our findings establish ZNF711 as a critical regulator of ENZR that promotes resistance by dually modulating the AR signaling pathway via transcriptional activation and epigenetic demethylation. Targeting the ZNF711-AR axis represents a novel therapeutic strategy to overcome ENZR in prostate cancer.

MUC14/Endomucin, a transmembrane mucin, is a potential prognostic biomarker in malignancies. This study aimed to elucidate the functional impact of MUC14 on tumor proliferation, migration, immune microenvironment modulation, and cisplatin response in lung adenocarcinoma (LUAD), and investigate its molecular mechanisms. LUAD cell lines with MUC14 overexpression (MUC14-OE) or silencing were constructed. Malignant behaviors were assessed via CCK-8, Transwell, and colony formation assays. Immune cell infiltration was quantified by CD3+/CD8 + immunohistochemistry. Subcutaneous xenograft and tail-vein metastasis murine models evaluated in vivo tumor progression and cisplatin responsiveness. Mechanisms were characterized using FRET and western blotting. Multiplatform bioinformatics analysis of public databases correlated MUC14 expression with clinical outcomes, immune infiltration, and chemotherapy response. MUC14-OE inhibited LUAD cell proliferation, migration, colony formation, and adhesion, while silencing promoted these phenotypes. MUC14 expression positively correlated with CD3+/CD8 + T-cell infiltration. In vivo, MUC14-OE suppressed subcutaneous tumor growth, lung metastasis, and enhanced cisplatin efficacy. Mechanistically, MUC14 inhibited integrin α8β6 clustering, suppressing PI3K/AKT and MAPK/ERK signaling. Cisplatin sensitization involved JNK/c-Jun pathway activation. This study establishes MUC14 as a multifunctional tumor suppressor in LUAD. It inhibits integrin α8β6-mediated PI3K/AKT and MAPK/ERK signaling to suppress tumor growth, promotes CD8+ T-cell infiltration, and augments cisplatin sensitivity via the JNK/c-Jun pathway. These findings nominate MUC14 as a prognostic biomarker and therapeutic target, suggesting combinatorial strategies integrating immunotherapy and chemotherapy.

Esophageal cancer is a highly aggressive malignant tumor of the digestive tract, with significant heterogeneity in its pathogenesis and clinical manifestations. Despite advances in treatment strategies such as surgery, chemotherapy, and radiotherapy, the prognosis of esophageal cancer remains poor. In recent years, increasing evidence has shown that epigenetic regulation plays a critical role in the occurrence and development of esophageal cancer. Epigenetic mechanisms, including DNA methylation, histone modification, and non-coding RNA, can regulate gene expression without changing the DNA sequence and are involved in a variety of biological processes, including cell proliferation, apoptosis, and invasion. Abnormal epigenetic alterations are not only key drivers of tumorigenesis but also promising biomarkers and therapeutic targets. This review focuses on the epigenetic mechanisms involved in esophageal cancer and summarizes the latest progress in epigenetic-based therapeutic strategies, including the development and application of DNA methyltransferase inhibitors, histone deacetylase inhibitors, and drugs targeting non-coding RNAs. Moreover, it discusses the challenges and future prospects of epigenetic therapy in the clinical management of esophageal cancer.

EphA2, a receptor tyrosine kinase, is overexpressed in various cancers. Its ligand-independent non-canonical signaling is pro-tumorigenic, and elevated EphA2 expression is associated with poor prognosis in patients. Although preclinical and clinical studies targeting EphA2 have been conducted as cancer therapeutics, its role in the DNA damage response remains elusive. This study examined the role of EphA2 in cell cycle progression in Adriamycin (ADR)-treated cells. ADR treatment transcriptionally upregulated EphA2 expression in a p53-independent manner. Suppression of EphA2 upregulation abrogated G2 arrest, as evidenced by reductions in both cyclin B1 accumulation and Wee1 inhibition-driven cell division. However, the 2N-G1 cell population remained low, with increased tetraploid cells. Time-lapse imaging revealed that tetraploid formation resulted from mitotic bypass rather than mitotic slippage or cytokinesis failure. EphA2 knockdown upregulated p21 expression together with p53, and p21 knockdown suppressed EphA2 knockdown-induced mitotic bypass. Monitoring fluorescence from a green fluorescent protein fusion with the cyclin B1 destruction box demonstrated degradation in interphase without cell division, suggesting premature activation of APC/CCdh1 in interphase. Notably, p21 upregulation following EphA2 knockdown was observed specifically in cervical cancer cell lines. Finally, ADR-induced suppression of cell proliferation was further enhanced by EphA2 knockdown and partially reversed by p21 knockdown. In conclusion, EphA2 suppression induces p21-dependent mitotic bypass and tetraploidization, leading to reduced cell proliferation. EphA2 upregulation following DNA damage may be pro-tumorigenic by maintaining G2 arrest to keep DNA damage at tolerable levels. These findings provide a rationale for combining EphA2 inhibition with DNA-damaging agents in certain cancer types.

Quercetin (Que) possesses diverse biological activities and has been extensively investigated in various fields, but its impact on rooster reproductive performance and the underlying mechanisms remains poorly understood. The present study investigated the effect of quercetin on reproductive performance of roosters and preliminarily explored its underlying regulatory mechanism. Forty-eight 100-day-old roosters were randomly divided into control group and three quercetin groups (Que_5mg/d, Que_10mg/d, and Que_20mg/d). Daily gavage was conducted continuously for 60 days. Semen quality was evaluated using a sperm analyzer. Then, metabolomics, proteomics, network pharmacology, molecular dynamics simulation, hormone detection, qRT-PCR, and their combination analysis was employed for mechanism validation. The result of semen quality evaluation and testicular tissue morphology observation showed that quercetin can significantly increase the semen collection volume, semen motility (P < 0.05), sperm density was significantly higher in the Que_5mg/d and Que_10mg/d groups than in the control group (P < 0.05), and the diameter of the seminiferous tubules, the height of the seminiferous epithelium of the testes (P < 0.05). Consistently, both testicular metabolomics and hormone detection results indicated that quercetin significantly increased testosterone levels (P < 0.05). Metabolite KEGG enrichment analysis revealed a significant upregulation of the steroid hormone biosynthesis. Proteomics and qRT-PCR assays confirmed that quercetin upregulated the expression of genes such as CYP11A1, CYP17A1, and molecular docking and molecular dynamics simulations further indicate that quercetin has a favorable binding with steroid hormone biosynthesis related protein CYP11A1. These results demonstrates that supplementation with quercetin at a dosage of 10 mg/d can enhances reproductive performance in roosters by targeting steroid hormone biosynthesis-related proteins to promote hormone synthesis.

Breast cancer remains the most common type of cancer affecting women. The estrogen receptor status of a tumor defines the therapeutic approach, which often includes endocrine treatment. Therefore, identifying potential endocrine-disrupting chemicals is of great importance.

Adiponectin and irisin regulate energy homeostasis and interact with peroxisome proliferator-activated receptor coactivator 1α (PGC-1α). However, whether they establish a signal connection via PGC-1α is unclear. In the current study, the expression of irisin was significantly decreased in the skeletal muscle of adiponectin knockout (KO) mice, accompanied by a de crease in APPL1/p38 mitogen-activated protein kinase (MAPK)/PGC-1α. However, adiponectin administration reversed this effect. In vitro, the p38 MAPK/PGC-1α signalling pathway mediated adiponectin-induced FNDC5 expression and irisin release in mouse-derived C2C12 myotube cells. Moreover, obesity caused dysregulation of the adiponectin/APPL1/p38 MAPK/PGC-1α signalling pathway in murine skeletal muscle, ultimately inhibiting irisin synthesis and secretion; meanwhile, prolonged exercise or exogenous recombinant adiponectin intervention activated this pathway in mouse skeletal muscle. This corresponded with an apparent improvement in high-fat diet-induced insulin resistance. The effect of mechanically stretching C2C12 myotube cells was consistent with in vivo findings. Hence, adiponectin upregulates irisin through the APPL1/p38MAPK/PGC-1α signalling pathway in murine skeletal muscle, which may enhance insulin sensitivity.

Cadmium (Cd) pollution adversely affects plant growth and development, leading to reductions in crop yields and posing a threat to human health. Selenium (Se) is an essential micronutrient for both humans and animals. Wheat, an important cereal crop, is particularly prone to accumulating Cd in polluted environments. However, there is a paucity of studies examining the mitigation mechanisms of Se on the photosynthetic systems of wheat leaves under Cd stress. In this study, the alleviating effect of Se on Cd toxicity in wheat was investigated. The results showed Se increased wheat biomass by 20 %-50 %, photosynthetic parameters by 26 %-55 %, chlorophyll content by 17 %-29 % and help to keep normal leaf structure under Cd stress. Se upregulated key starch anabolism genes TaAGPS1, TaSUT2, and TaSWEET15 expression level, and thus complemented soluble sugar content by 16 %-21 %, starch content by 15 %-59 % disturbed by Cd stress. Under Cd stress, Se decreased wheat shoot Cd content by 6 %-19 %, and increased shoot Fe, Mn, Zn content by 5-28 %, 23-58 %, 8-32 %, respectively. These results suggest that Se mitigates Cd stress in wheat by limiting Cd translocation to shoots and regulating the expression of key carbon metabolism genes.

Benzo(a)pyrene (B(a)P), a prominent environmental carcinogen, is known to promote lung cancer progression; however, its underlying mechanistic pathways remain poorly defined. Here, we identify the EP300-H2BK5ac epigenetic axis as a key regulator of membrane surface tension and epithelial-mesenchymal transition (EMT) in lung cancer cells under B(a)P exposure. Using A549 and SW900 cells, we demonstrate that B(a)P treatment induces a dose-dependent reduction in membrane tension and promotes EMT, migration, and invasion. Mechanistically, B(a)P downregulates EP300 expression, leading to decreased H2BK5ac acetylation and impaired binding of H2BK5ac to the promoter of the endocytosis-related gene HSPA1A, as revealed by co-immunoprecipitation and ChIP-qPCR. EP300 knockdown mimics these effects, enhancing malignant behaviors, whereas EP300 overexpression restores H2BK5ac levels, increases HSPA1A expression, and suppresses B(a)P-induced phenotypes. Notably, HSPA1A overexpression in EP300-deficient cells partially rescues membrane tension and reverses EMT progression. These findings uncover a previously unrecognized EP300-H2BK5ac-HSPA1A regulatory pathway that links environmental exposure to biomechanical and epigenetic remodeling in lung cancer. Targeting this axis may offer new strategies to mitigate B(a)P-driven metastasis.

Nitrogen (N) plays a crucial role in enhancing plant growth and stress tolerance, but the physiological mechanisms and multi-omics evidence underlying its effect on cadmium (Cd) accumulation and detoxification in woody plants have not been fully understood. In this study, by integrating physiological, transcriptomic, metabolomic, and rhizobacterial analyses, the effects of NH4HCO3-based N fertiliser on 3-month-old poplars subjected to Cd stress were investigated to determine its potential for bioaccumulation and detoxification. Exogenous N significantly enhanced the Cd uptake efficiency and Cd content in whole plants by 93.79 and 160%, respectively, compared to the Cd-only group. N selectively recruited Bacillus, Fictibacillus, and Nitrospira, which are associated with a reduced soil pH, increased Cd bioavailability, and phytohormones (brassinolide and zeatin) biosynthesis, facilitating plant growth and Cd absorption. Concurrently, multi-omics analyses revealed the upregulation of genes involved in reduced glutathione (GSH) and phytohormones biosynthesis, antioxidant defence, and Cd transport and chelation (e.g., PyGCLC, PyGSS, PyDWF, PyIPT, PyAPX, PyCAT, PyNRAMP, PyMT, PyHIPP). Consistently, the accumulation of GSH, key amino acids (cysteine, glutamate, glutamine), phytohormones, flavonoid derivatives (eriodictyol, dihydrokaempferol, glyceollin II), and osmoprotectants (proline, soluble sugars) and the activities of antioxidant enzymes (catalase, superoxide dismutase, peroxidase, ascorbate peroxidase) were enhanced. Thus, Cd-induced reactive oxygen species and lipid peroxidation were reduced, and Cd accumulation and detoxification-related responses were enhanced. These findings suggest that N improves the phytoremediation efficiency of poplar by affecting the rhizosphere environment and Cd bioavailability and by modulating physiological and metabolic processes in plant cells.

The bZIP transcription factor ABI5 (Abscisic acid insensitive 5) plays a central role in regulating responses to ABA (Abscisic acid) signals during seed germination and early growth. In Arabidopsis thaliana, ABI5 is strongly induced by ABA, and high ABI5 expression inhibits seed germination. Plant MYB (Myeloblastosis) proteins respond to multiple hormonal signals, including ABA. Moreover, many R2R3 MYB transcription factors show functional similarities to ABI5; however, regulation of ABI5 transcriptional activity by R2R3 MYB factors during seed germination remains insufficiently characterized. In this study, we found that BoMYB96 and BoMYB2 bind the BoABI5 promoter and inhibit its transcription. A. thaliana and Brassica napus lines overexpressing BoMYB96 or BoMYB2 exhibited ABA insensitivity when exposed to exogenous ABA, which increased rapeseed germination rates under ABA treatment. These results demonstrate functional conservation of AtMYB96 and AtMYB2 in ABA signaling and expand understanding of ABI5 transcriptional regulation in the genomes of Brassica oleracea and B. napus.

Seed priming with engineered nanoparticles can promote seed germination. Herein, we investigated how priming seeds with antioxidant poly(acrylic acid)-coated cerium oxide nanoparticles (PNC, 0.05 mM) impacts seed germination in cotton (Gossypium hirsutum L.). Seed priming with PNC significantly increased cotton hypocotyl elongation by 13 %-37 %, promoting seed germination in pot experiment. Meanwhile, the emergence rate increased by 15 %-16 % with 0.05 mM PNC-seed priming in the field. Transcriptome analysis identified PNC-induced differentially expressed genes (DEGs) related to the phytohormone, auxin (IAA), and brassinosteroid (BR) biosynthesis (e.g. GhTAA1, GhYUCCA, GhALDH, GhGH3, GhCYPs) and signal transduction (e.g. GhSAUR, GhBZR1). Consistently, PNC priming increased the accumulation of IAA (10 %-25 %) and BR (86 %-100 %) in cotton hypocotyls. In addition, PNC enhanced the expression of the xyloglucan endotransglucosylase/hydrolase (XTHs) genes, regulated by SAUR and BZR1 through IAA and BR signaling pathway and critical for cell elongation. Also, the cell lengths of the epidermis, endodermis, xylem, and pith in cotton hypocotyl increased by 21 %, 17 %, 31 %, and 21 %, respectively upon seed priming with 0.05 mM PNC. The results provide insights into the molecular mechanisms of nanoparticles-seed priming enhancement of plant seed gemination.

Soil alkalinity and heavy metal toxicity are major abiotic stresses that severely limit plant growth and crop productivity. Wild soybean (Glycine soja) exhibits strong alkaline tolerance, making it a valuable genetic resource for improving cultivated soybean. Previous studies identified Gshdz4 and GsNAC019 as key alkaline-tolerant transcription factors, and GsEXPA8 as an alkaline-tolerant expansin protein. This study establishes a hierarchical "nucleus-nucleus-membrane" regulatory model in wild soybean, wherein the nuclear master transcription factor Gshdz4 transcriptionally upregulates GsNAC019, which in turn activates the expression of the plasma membrane-localized expansin GsEXPA8, collectively enhancing alkaline tolerance. We further investigated the role of Gshdz4 in conferring resistance to combined sodium bicarbonate and cadmium chloride stress in soybean. Through integrated RNA-seq and CUT&Tag-seq analyses, we identified Gshdz4 as a direct binder and regulator of diverse stress-responsive genes-including GmDEAH5, GmHSP22.3, GmACR4, and GmATG1c. Under alkaline stress, Gshdz4 modulates GmSLX8, GmSF3, and GmPP4; under cadmium stress, it regulates GmGMFL01 and GmUNC, establishing a broad-spectrum defense mechanism. Additional targets encompass splicing factors, heat shock proteins, ABA signaling components, and ethylene-responsive factors. GO and KEGG enrichment analyses confirmed that Gshdz4 participates in multiple hormonal pathways (ABA, IAA, ET, JA) and stress response signaling. Our findings revealed Gshdz4 as a master transcriptional regulator under multiple stresses and provide a theoretical foundation for molecular breeding strategies to enhance soybean resilience.

Cd contamination poses significant ecological risks. Quercus dentata, a tree species of high ecological value, exhibits exceptional tolerance to adverse environmental conditions. This study used Q. dentata as material to investigate its physiological response characteristics and potential molecular mechanisms under different concentrations of Cd stress (0, 200, 400, 600 mg/L). Results showed that with increasing stress concentration, the growth and photosynthesis parameters of Q. dentata continued to decline, while cell membrane permeability parameters, antioxidant enzyme activities, osmoregulatory substances, and Cd accumulation in various tissues continued to increase. Transcriptome sequencing also showed significant enrichment of photosynthesis, oxidative stress, amino acid synthesis, and ion binding-related genes (RBOH, SOS, POD). Based on the transcriptomic analysis, we found that numerous transcription factors (MYB, AP2, and WRKY) and heavy metal transport proteins (MTP, OPT, and HMP) played significant roles in the molecular mechanisms of Q. dentata's response to Cd stress. According to qPCR results, we identified the key gene QdMTP10.3, whose expression was continuously upregulated in different tissues with increasing treatment concentrations, conferring Cd2+, Fe2+, and Mn2+ tolerance to yeast cells. In summary, it is concluded that Q. dentata enhances its tolerance to Cd stress by modulating plasma membrane permeability, osmoregulatory substance content, and antioxidant enzyme system activity, while QdMTP10.3 gene plays a pivotal role in Cd response to heavy metal stress similarly, conferring potential for genetic improvement of heavy metal tolerance in plants.

Cadmium (Cd), a highly toxic element, poses significant constraints on global crop distribution and productivity. A better understanding of the molecular mechanisms underlying the response to Cd stress will help improve plant performance under Cd-exposed conditions. Here, we aimed to elucidate the complex response mechanisms of two oat varieties (CEav5651 and T1402) to Cd stress through integrated metabolomic and transcriptomic analyses. Our findings demonstrated that CEav5651 exhibited superior Cd tolerance compared to T1402. Metabolomic profiling revealed that glutathione and nicotianamine levels were significantly elevated in both varieties under Cd stress, with CEav5651 accumulating substantially higher concentrations of these two metabolites than T1402. This differential accumulation was corroborated by corresponding transcriptomic alterations. Critically, exogenous application of glutathione or nicotianamine markedly enhanced plant Cd tolerance. Heterologous overexpression of AsGS3 and AsNAS17, key genes in glutathione and nicotianamine biosynthesis, respectively, in tobacco (Nicotiana tabacum) elevated endogenous levels of these metabolites and conferred enhanced Cd tolerance. Our findings reveal the pivotal, coordinated role of glutathione and nicotianamine metabolism in Cd tolerance and provide promising genetic targets for breeding resilient crops.

Plants have evolved intricate and sophisticated mechanisms to sense and respond to boron (B) stresses. Alterations to the cell wall and other molecular pathways are strategies that help plants adapt to B stresses by cross-linking with rhamnogalacturonan II (RG-II) to form borate-dimers. However, the molecular mechanism by which cell wall components and organization respond to B stresses is not fully understood in mulberry plants. This study, via conjoint transcriptomics-metabolomics and virus-induced gene silencing analyses, aimed to explore the diverse B stress response mechanisms and functionally characterize the role of MaXTH23 in cell wall remodeling in mulberry leaves subjected to different levels of B, ranging from deficiency (0 mM; T1), sufficiency (0.1 mM; control, CK), moderate deficiency (0.02 mM; T2), toxicity (0.5 and 1.0 mM as T3 and T4, respectively) and cultivated under greenhouse conditions. The analyses identified a total of 6114 and 441 differentially expressed genes (DEGs) and metabolites (DEMs), respectively, in the different KEGG pathways in the separate omics analysis for all treatments. However, our conjoint analysis identified 1120 DEGs associated with 78 DEMs and were significantly co-enriched in 96 different KEGG pathways. Meanwhile, the functional characterization via silencing of MaXTH23 did not nullify its function in cell wall modification and remodeling but concomitantly caused significant increases in total pectin and water-soluble pectin contents, quintessentially promoting pectin cross-linking in the cell wall. This study highlights a novel perspective for identifying and characterizing the regulatory functions of MaXTH23 and the B-induced pathways and tolerance mechanisms employed by mulberry plants.

In an attempt to identify markers that better characterize microglial states and to search for potential therapeutic targets, we performed a study using the IMG cell line as an in vitro microglial model. Specifically, we tested its response to several pro-inflammatory stimuli (lipopolysaccharide, interferon gamma, and tumor necrosis factor) and an anti-inflammatory stimulus (Interleukin-4) after 12 and 24 h of incubation. We performed RNA sequencing to identify genes modified at both incubation times (i.e., genes with sustained changes in the window between 12 and 24 h) that could reflect sustained microglial transcriptional responses. We also used Gene Ontology (GO) analysis to identify the most relevant pathways modified by these stimuli. RNA sequencing revealed four gene sets: (1) common genes that respond similarly to IL-4 and LPS, (2) specific LPS responders, (3) specific IL-4 responders, and (4) genes that exhibit LPS-induced upregulation and IL-4-induced downregulation, and vice versa (opposite responders). We hypothesize that the common gene set represents a general microglia response to pathological conditions, while the LPS- and IL-4-responder gene sets define specific microglial states under pro- and anti-inflammatory stimuli, respectively. We further propose that opposite responder genes act as metabolic switches between certain microglial states. The GO analysis indicated that LPS strongly upregulates biological processes related to the innate immune response, while IL-4 upregulates pathways related to repair, metabolic reprogramming, and cellular cooperation. Finally, the transcriptional response of IMG cells closely mirrored that of primary microglia, revealing highly similar gene expression and GO term profiles under LPS stimulation.

GATA6 promotes epithelial phenotypes and limits epithelial-to-mesenchymal (EMT) transition in pancreatic ductal adenocarcinoma (PDAC). Here we show that GATA6 defines a tumor cell state that induces MHCI expression and anti-tumor cytotoxicity upon therapy. In human PDAC, GATA6 expression correlates with immune cell infiltration, and spatial analysis reveals interaction between GATA6+ tumor cells and CD8+ T cells. In murine PDAC, MEK inhibition (MEKi) enriches antigenicity-related gene sets in GATA6high cells, while GATA6 knockout or degradation impairs MEKi-induced MHCI upregulation. High-GATA6 tumors respond to MEKi with increased MHCI, enhancing T-cell cytotoxicity, whereas GATA6 loss abolishes this effect. Treatment-induced EMT reduces GATA6+ populations and MHCI expression, which is restored by combining MEKi with HDAC inhibitors, enhancing GATA6+ tumor cells, MHCI, CD8+ T cell infiltration, tumor suppression, and survival. These findings suggest that therapeutic strategies promoting a GATA6-driven tumor cell state improve immune recognition of PDAC cells and potentiate anti-tumor cytotoxic effects.

This study explores the bioactivity and intestinal absorption of peptides from Acheta domesticus (house cricket), emphasizing their potential health benefits and relevance to sustainable protein sources. Six peptides (DVW, AVQPCF, QIVW, CAIAW, PIVCF, and IIIGW) obtained from the simulated gastrointestinal digestion of the A. domesticus proteins acyl-CoA Delta12-desaturase, acyl-CoA Delta-9 desaturase and diuretic hormone receptor were assessed for their effects on gene expression markers related to diabetes (DPP-4, SGLT1) and hypertension (sACE, ACE2). Using Caco-2 cells to model intestinal absorption, the peptides were evaluated for transport, cytotoxicity, and impact on barrier integrity. All peptides were non-cytotoxic up to 2 mM; however, DVW and PIVCF disrupted epithelial integrity. Only DVW crossed the epithelium intact. While none of the peptides significantly affected sACE or ACE2 expression, DVW and PIVCF notably downregulated SGLT1 expression (to 0.42- and 0.52-fold, respectively), suggesting potential antidiabetic effects through reduced glucose absorption.

Bevacizumab (Bev) resistance limits therapeutic efficacy in ovarian cancer (OC) patients. We identified ESM1 as a key gene in Bev-resistant OC. ESM1 secreted by OC-resistant cell lines activates the ITGB1/FAK axis to induce neovascularization and Bev resistance. Additionally, ESM1 overexpression promoted the growth and Bev resistance of OC, lung, intestinal, and hepatocellular carcinoma tumors. Then, we identified TRIM28 as an upstream regulator that stabilizes ESM1 by promoting SUMOylation, inhibiting its proteasomal degradation. In OC mice, TRIM28 overexpression promotes angiogenesis and Bev resistance via ESM1-mediated ITGB1/FAK activation. This work unveils a new molecular pathway underlying Bev resistance in OC and proposes TRIM28 and ESM1 as potential therapeutic targets.