Ferroptosis, an iron‑dependent form of programmed cell death, is a promising target for cancer therapy. Peptidyl‑prolyl cis/trans isomerase 1 (PIN1), a member of the peptidyl‑prolyl cis/trans isomerase family, is often overexpressed in cancer and contributes to tumor cell proliferation, survival and metastasis. The present study investigated whether PIN1 regulates ferroptosis in gastric cancer (GC). GC cell models with either PIN1 knockdown or overexpression were established and treated with the ferroptosis inducer erastin, followed by assessment of cell viability and proliferation rate using Cell Couting Kit‑8 and colony formation assays, detection of PIN1 and cytoplasmic polyadenylation element binding protein 1 (CPEB1) expression via western blotting and reverse transcription‑quantitative PCR, and evaluation of glutathione peroxidase 4 (GPX4) expression through immunofluorescence assay. Experimental results indicate that PIN1 depletion increases erastin‑induced ferroptosis, as evidenced by increased levels of reactive oxygen species, malondialdehyde and intracellular free iron. PIN1 overexpression attenuates the erastin‑induced ferroptotic response, as evidenced by decreased levels of ferroptosis‑related biomarkers. Further analysis reveals that silencing PIN1 upregulates CPEB1, which, in turn, suppresses GPX4 expression. Simultaneous knockdown of CPEB1 reverses the ferroptosis‑enhancing effect of PIN1 depletion. These mechanistic findings suggest that PIN1 promotes GPX4 expression by repressing CPEB1, thus inhibiting Erastin‑induced ferroptotic cell death in GC. In vivo experiments further suggest that PIN1 knockdown significantly reduces the tumorigenic potential of GC cells. A novel PIN1‑CPEB1‑GPX4 axis was identified, in which PIN1 downregulates CPEB1 to mediate ferroptosis resistance. This axis represents a potential therapeutic target, as PIN1 knockout demonstrates significant tumor suppression in animal models. The present study identifies a novel PIN1‑CPEB1‑GPX4 regulatory axis that controls ferroptosis, suggesting its potential as a therapeutic target for advanced GC.

As a transcriptional co-factor of E2F, DP proteins are typically involved in the regulation of plant cell-cycle-related processes. However, whether DP proteins participate in transcriptional regulation associated with plant antiviral defence remains largely unclear. This study demonstrates that NbDPB, a DP family protein in Nicotiana benthamiana, positively regulates resistance to potato virus X (PVX) by functioning as a transcription factor. Knockout of NbDPB increased plant susceptibility to PVX, while its overexpression significantly suppressed viral accumulation. Furthermore, we identified that NbDPB binds to the promoter of NbMYB (a MYB transcription factor) and positively regulates its expression. Silencing NbMYB enhanced PVX infection, whereas exogenous application of jasmonic acid (JA) and salicylic acid (SA) partially rescued this phenotype. Hormone levels of JA and SA, as well as the expression levels of their marker genes, were significantly reduced in the silenced NbMYB plants. These findings suggest that the NbDPB-NbMYB module mediates antiviral defence through the JA and SA signalling pathways. This study reveals a previously uncharacterized role of DP proteins in antiviral transcriptional regulation, indicating that they may play a crucial role in plant antiviral defence.

Quinclorac is widely used in rice cultivation; however, its persistent residue poses a serious risk to subsequent tobacco crops in rice-tobacco rotation systems, limiting the sustainability of this practice. Although rice and tobacco exhibit markedly different sensitivities to quinclorac, the molecular basis for this divergence remains unclear. In this study, we investigated the differential molecular mechanisms from stress perception to phenotypic response by integrating comparative transcriptomics, physiological profiling, and metabolic pathway analysis. Under quinclorac, the tobacco cultivar K326 (K326) suffered severe growth inhibition and oxidative damage, whereas the rice cultivar Nipponbare (NPB) maintained internal homeostasis. Comparative transcriptomics analysis revealed putative distinct response strategies. K326 may activate a defense response program characterized by strong induction of mitogen-activated protein kinase (MAPK) and ethylene/jasmonic acid signaling pathways, followed by large-scale transcriptional reprogramming dominated by MYB and WRKY transcription factors. In contrast, NPB may adopt a steady-state prioritization strategy, upregulating NAC transcription factors to enhance glutathione-based detoxification while sustaining the core metabolic processes, including photosynthesis. Collectively, our work provides a systematic framework for understanding the molecular basis of the differential quinclorac response in rice and tobacco.

Fetal Alcohol Spectrum Disorder (FASD) presents a profound global health burden, yet clinical diagnosis remains severely hindered by phenotypic heterogeneity and the lack of objective biomarkers. Emerging evidence reveals that the pathogenesis of prenatal alcohol exposure (PAE) is heavily driven by fetal programming via epigenetic modifications. In this narrative review, we synthesize data from human cohorts and advanced preclinical models to conceptualize FASD as a dynamic epigenetic trajectory rather than a static teratogenic insult. Ethanol disrupts the epigenome systemically, perturbing one-carbon metabolism, oxidative stress pathways, non-coding RNAs, and the placenta-brain axis. Furthermore, postnatal environmental factors, particularly early-life stress, interact with PAE to shape neuroimmune vulnerability and sexually dimorphic outcomes. While stable peripheral DNA methylation "episignatures" offer significant promise for future risk stratification, we highlight the critical translational challenge of correlating these peripheral markers with central neuropathology. Although AI-assisted screening and targeted epigenetic interventions (e.g., choline supplementation) represent exciting translational avenues, they remain investigational. Ultimately, transitioning FASD toward precision medicine will require longitudinal, single-cell multi-omic studies to validate tissue-specific biomarkers, address ethical and algorithmic biases, and pave the way for biologically grounded, early interventions.

Breast cancer remains a significant clinical challenge, with treatment failure and patient mortality primarily attributable to tumor metastasis. Daucosterol linoleate (DL) was previously isolated from sweet potato (Ipomoea batatas). Using HPLC analysis of ten commercial dried sweet potato products from different regions of China, DL was detected in all samples, with concentrations ranging from 1.24 mg to 6.05 mg per 100 g, confirming its widespread presence in commercially processed sweet potato products. Pharmacokinetic analysis showed that DL exhibited a peak plasma concentration (Cmax) of 1452.28 ng/mL, an elimination half-life (t1/2) of 11.14 h, and a mean residence time (MRT) of 9.62 h, supporting its potential for oral administration. DL significantly suppressed proliferation and migration of MCF-7, 4T1, and MDA-MB-231 cells in vitro and reduced lung metastasis in vivo. Proteomic analysis identified SCD1 as a key molecule mediating the effects of DL. Mechanistically, DL downregulated SCD1 to inhibit epithelial-mesenchymal transition (EMT), as evidenced by decreased expression of N-Cadherin, MMP2, Vimentin, and Snail, alongside increased E-Cadherin expression. Collectively, DL inhibits breast cancer metastasis by downregulating SCD1 and suppressing EMT, supporting its dual potential as a functional food ingredient and adjuvant therapeutic.

Advanced glycation end products (AGEs) and their receptor receptor for AGEs (RAGE) promote tumor progression via activation of the nuclear factor-kappa B (NF-κB) signaling pathway. Although 3-Hydroxyflavone exhibits anticancer properties, its role in oral squamous cell carcinoma (OSCC) and its interaction with the AGEs/RAGE/NF-κB axis remain unclear.

Volatile anesthetics, particularly sevoflurane, have demonstrated cardioprotective properties during cardiac surgery. However, their immunomodulatory mechanisms at the molecular level remain unclear. Given the close relationship between cardiac injury and immune responses, understanding how anesthetic agents influence immune-related pathways may provide new insights into perioperative myocardial protection. This study aimed to explore the immunological and molecular mechanisms underlying the effects of sevoflurane anesthesia on cardiomyocytes in patients undergoing coronary artery bypass grafting (CABG). Gene expression data (GSE4386) from myocardial tissues of CABG patients anesthetized with sevoflurane or propofol were analyzed. Differentially expressed genes (DEGs) were identified using R software, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein-protein interaction networks were constructed to identify key immune-associated hub genes. A total of 211 DEGs were identified. Functional enrichment revealed that these genes were predominantly associated with immune and inflammatory processes, including leukocyte activation, cytokine-cytokine receptor interaction, neutrophil extracellular trap formation, and chemokine signaling pathways. Hub genes such as ITGAM, PTPRC, TYROBP, TLR2, and TLR4 were identified as central immune regulators potentially mediating the cardioprotective and immunomodulatory effects of sevoflurane. Sevoflurane anesthesia may confer myocardial protection after CABG by modulating immune-related signaling pathways and inflammatory gene expression. These findings highlight the immunoregulatory potential of volatile anesthetics, providing novel perspectives for immune-targeted strategies in perioperative cardiac management.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, for which effective therapeutic strategies remain limited. AdipoRon, a synthetic adiponectin receptor agonist, has been reported to possess anti-inflammatory properties. In this study, we evaluated the therapeutic potential and underlying mechanisms of AdipoRon in alleviating RA-related synovial inflammatory lesions. In an adjuvant-induced arthritis (AIA) rat model, AdipoRon treatment markedly improved clinical scores and reduced ankle swelling. Histological and micro-CT evaluations demonstrated AdipoRon alleviated synovial inflammatory lesions, cartilage degradation, and bone erosion. In vitro, AdipoRon dose-dependently suppressed TNF-α-induced proliferation, migration, and invasion of fibroblast-like synoviocytes (FLSs). RNA sequencing identified Keratin 7 (Krt7) as a key gene responsive to AdipoRon. Immunofluorescence analysis confirmed upregulated Krt7 expression in RA patient samples. Functional studies demonstrated that Krt7 overexpression promoted synovial inflammation and FLSs migration and invasion, whereas AdipoRon alleviated these pathological processes by downregulating Krt7. Collectively, these results demonstrate that AdipoRon ameliorates synovial inflammation and abnormal FLSs activation by modulating Krt7, therefore supporting its further development as a therapeutic candidate for RA.

The phytohormone abscisic acid (ABA) promotes seed dormancy, inhibits seed germination, and induces post-germination growth arrest. It remains unclear how chromatin remodeling influences ABA responses during early seedling establishment. In this study, an artificial microRNA targeting 2 sucrose nonfermenting 2 (SNF2)-family chromatin remodeling ATPases, SPLAYED (SYD) and PHOTOPERIOD-INDEPENDENT EARLY FLOWERING1 (PIE1), was identified through unbiased forward genetic screening of artificial microRNA (amiRNA)-expressing pooled seed libraries exhibiting ABA insensitivity during the seed-to-seedling transition. T-DNA insertional mutants of syd and pie1, along with amiRNA-expressing knockdown lines amiR-SYD and amiR-PIE1, confirmed that SYD is required for ABA inhibition of post-germination growth. Transcriptomic analyses revealed that, under ABA treatment, amiR-SYD mutant seeds exhibited increased expression of the ABA catabolism gene CYP707A3 and the gibberellin (GA) biosynthesis genes GA20OX2, GA20OX3, GA3OX1, GA3OX2, and GA3OX4. Concurrently, the ABA-responsive genes KIN1 and EM6 were less strongly induced, whereas the GA-responsive genes GASA4 and GASA6 were more strongly induced. The ABA hyposensitivity observed in amiR-SYD mutants was reversed by treatment with uniconazole, an inhibitor of ABA catabolism and GA biosynthesis. These findings suggest that the SYD-associated chromatin remodeling complex positively regulates ABA-mediated post-germination growth arrest by modulating the balance between ABA and GA responses, in contrast to its close homolog BRAHMA (BRM), which negatively regulates ABA responses through an ABI5-mediated checkpoint.

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. Although anti-angiogenic agents like Axitinib are used in cancers, resistance emerges through poorly understood mechanisms involving stemness and vasculogenic mimicry (VM). Here, we investigated the regulatory role of thrombospondin-1 (THBS1), an anti-angiogenic protein, in Axitinib-mediated signaling and its impact on TNBC. The effects of Axitinib on VM, angiogenesis, and stemness in TNBC were investigated through in vivo models and in vitro endothelial-supernatant cultures. Bioinformatics analyses (GSE230643 and CellChat), immunohistochemistry of clinical samples, exosome transfer assays, and xenograft models were employed to explore how Axitinib regulates THBS1-mediated endothelial-TNBC intercellular communication. Further bioinformatics analyses, combined with in vitro and in vivo experimental validations, were performed to elucidate the mechanism of the THBS1-CD47 axis in TNBC. Axitinib treatment increased stemness and promoted VM in TNBC models, despite tumor growth inhibition. Bioinformatics analyses revealed the Axitinib-dependent THBS pathway between endothelial and endothelial-like tumor cells. Axitinib-induced downregulation of THBS1 expression in HUVEC cells promoted stemness and angiogenesis of recipient TNBC cells via exosomes. Mechanistically, endothelial-derived THBS1 promoted CD47 expression in recipient TNBC cells, thereby attenuating the activity of PI3K/Akt and MAPK/ERK signaling pathways, and inhibiting stemness, angiogenesis, and VM. Importantly, Axitinib disrupted this THBS1-CD47 axis by downregulating endothelial-derived THBS1 expression. Axitinib induces the suppression of THBS1 expression in endothelial cells, thereby enhancing stemness and VM in recipient TNBC via disruption of the THBS1-CD47 axis. Restoring THBS1 signaling may represent a promising strategy to overcome Axitinib resistance.

Epigenetic deregulation is a hallmark of myeloid malignancies, shaping their initiation, progression, and therapeutic response. Unlike genetic alterations, epigenetic modifications, such as DNA methylation, histone acetylation, and chromatin remodeling, are reversible, making them attractive targets for pharmacological intervention. This chapter aims to provide a detailed and comprehensive overview of epigenetic drugs currently available in both preclinical and clinical testing, with a particular focus on agents directed against histone deacetylases (HDACs), DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone demethylases (HDMs), bromodomain and extra-terminal (BET) proteins, and mutant IDH1/2 enzymes. By detailing the mechanisms of action and the available translational data for these pharmacological agents, the chapter aims to summarize the current state of epigenetic therapy and highlight how the development of epigenetic therapies is shaping the clinical landscape of myeloid malignancies.

Triclosan (TCS), an antimicrobial agent widely incorporated in personal care products, has become a persistent aquatic contaminant, posing potential risks to freshwater organisms. This study examined sub-lethal TCS toxicity in Labeo rohita, demonstrating its capacity to disrupt oxidative balance, hematology, antioxidant defenses, and induce multi-organ damage. Fish were exposed for 6 weeks to two concentrations of TCS: 0.0742 mg/L (T1) and 0.148 mg/L (T2), representing one-tenth and one-fifth of the 96-h LC₅₀, respectively, under semi-static conditions. At each sampling interval, one fish from each replicate tank was sampled for biochemical, histopathological, and qRT-PCR analyses (n = 3 biological replicates per treatment group). TCS exposure induced significant (p < 0.05), dose- and time-dependent oxidative stress, evidenced by increased reactive oxygen species (ROS), reduced hemoglobin (Hb) and red blood cells (RBCs), and elevated white blood cells (WBCs). Antioxidant responses showed increased superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (LPO) and decreased reduced glutathione (GSH), following the organ-specific severity order: gill > kidney > muscle. Gene expression analysis via qRT-PCR indicated a clear shift in autophagy-related markers, showing elevated levels of atg5, beclin1, lc3, and ulk1b, along with reduced mTOR expression, suggesting enhanced autophagic activity under TCS-induced oxidative stress. The response displayed tissue-specific variation, with gill showing the greatest sensitivity, followed by kidney and muscle. Histopathological damage increased dose-dependently: T1 showed mild gill, kidney, and muscle lesions, whereas T2 exhibited severe gill oedema and aneurysm, marked renal degeneration, and extensive muscle fiber disruption. Pearson correlation analysis showed strong links among oxidative stress, hematological alterations, antioxidant responses, and alterations in gene expression. Altogether, TCS induced clear dose-dependent toxicity in L. rohita, highlighting its significant chronic ecological risk to freshwater systems even at low concentrations.

While dopamine is a monoamine neurotransmitter best known for its roles in reward, motivation, and motor function in the central nervous system, its actions extend beyond neurons and can influence non-neuronal cells via epigenetic mechanisms. An increasing body of literature demonstrates that dopamine signaling is important in immune cells, which express dopamine receptors (DRD1-DRD5) as well as the molecular machinery for dopamine synthesis and metabolism. Dopamine can regulate inflammatory activity, cell trafficking, and disease pathology, yet the epigenetic mechanisms underlying these effects remain poorly understood.

Pharmacotherapy induces complex molecular reprogramming in cancer, driving transcriptome-wide alterations and widespread dysregulation of alternative splicing. Despite these profound changes, there remain limited resources characterizing drug-induced whole-transcriptomic responses in cancer. Furthermore, while aberrant splicing can generate immunogenic neoantigens, existing resources fail to systematically integrate drug perturbations, splicing dynamics, and neoantigen landscapes. To address this gap, the DRIVE database was constructed as a comprehensive resource detailing drug-induced transcriptomic and splicing responses. Utilizing the large language models for rigorous metadata curation and construct the standardized processing pipeline, thousands of publicly available raw transcriptomic datasets from drug-treated and control cancer cell lines were systematically processed. The resulting repository encompasses 3,911 samples, involving 278 drugs and 272 cell lines, enabling the precise quantification of differential gene expression, differential alternative splicing events, and the prediction of splicing-derived human leukocyte antigen-binding peptides. Analysis of the data revealed that drug-induced transcriptomic reprogramming is highly context-dependent and correlated with chemical structural similarity. We identified Osimertinib as a potential immunomodulatory agent associated with transcriptional signatures of an activated tumor microenvironment, while KB-0742 emerged as an unappreciated candidate global splicing modulator. Furthermore, our large-scale prediction of differential splicing-derived neoantigens uncovered several drugs that warrant further investigation as candidates for combination immunotherapy. DRIVE also provides a user-friendly interface to browse datasets, perform drug enrichment and connectivity analysis. (https://componclab.com/DRIVE). This database could improve our understanding of molecular reprogramming under pharmacotherapy, and serve as a valuable platform for deciphering drug mechanisms, promoting virtual cell modeling and discovering novel strategies of drug repurposing.

The present study investigates the impact of dietary fucoidan supplementation on growth performance, intestinal tract morphology, endogenous digestive enzymes, hematological parameters, serum biochemical indices of Nile tilapia (Oreochromis niloticus), oxidative biomarkers, and related gene expressions. Fish weighing 2.54 ± 0.12 g had randomly assigned them into five groups of equal size (20 fish each aquarium), with three replicates per group. The fish were fed for 70 days with five experimental diets formulated: T1: Control (fucoidan 0 mg kg-1); T2: 0.5 mg kg-1 fucoidan; T3: fucoidan 1.0 mg kg-1, T4: fucoidan 1.5 mg kg-1 and T5; fucoidan 2.0 mg kg-1. At the end of the experiment, growth indices, feed utilization, digestive enzyme activity, intestinal histomorphometric, hematological indices, serum biochemical indices, and antioxidant enzyme activities were significantly (P < 0.05) increased in the groups fed diets supplemented by fucoidan, with the superiority of fish fed 2 mg kg-1 compared to the basal diet. Additionally, a control diet has the highest ALT and AST compared to other diets supplemented with different fucoidan levels. Fish fed either 1.5 mg kg-1 or 2.0 mg kg-1 fucoidan recorded the higher (P < 0.05) hematological parameters as WBCs, RBCs, neutrophils, lymphocytes, monocytes, and eosinophils. A diet supplemented with 2 mg kg-1 diet fucoidan displayed the highest gene expression of the inf-γ and il-1β, while the heat shock protein 70 (hsp70) gene was down-regulated. Overall, our results highlight the efficacy of fucoidan in increasing growth performance, feed utilization, antioxidant enzyme activity, and gene expression. Therefore, it can be considered a promising feed additive for tilapia farming.

The ripening of fleshy fruits is a highly complex process characterized by changes in quality attributes such as sugar, acid, and anthocyanin content. Among these, the levels of major organic acids (citric and malic acids) are crucial determinants of fruit taste quality. However, the mechanisms underlying the biosynthesis and metabolism of organic acids (citric and malic acids) in strawberries-especially those influenced by ethylene signaling-remain inadequately understood. This study elucidates the ethylene-mediated regulation of organic acid (citric and malic acids) metabolism in strawberry fruits through the FaMAP3K-FaERF13-FaKAT module. We identified FaERF13 as a key transcription factor that directly binds to and represses the FaKAT promoter (electrophoretic mobility shift assay, yeast 1-hybrid, luciferase reporter assay), thereby promoting the accumulation of total organic acids. Comparative analysis of red ("Benihoppe") and white ("Snow Princess") cultivars revealed that this regulatory mechanism is consistently observed, although post-translational modifications likely explain the acid reduction in ripening "Snow Princess" despite high FaERF13 expression. Protein interaction studies (yeast 2-hybrid, co-immunoprecipitation, bimolecular fluorescence complementation) demonstrated that FaMAP3K physically interacts with FaERF13, forming a signaling cascade that fine-tunes the homeostasis of organic acids (citric and malic acids). Functional validation in strawberry and tobacco systems confirmed that FaMAP3K enhances FaERF13-mediated FaKAT suppression. These findings establish a dual-layer regulatory network in which ethylene coordinates both transcriptional (FaERF13-FaKAT) and post-translational (FaMAP3K-FaERF13) control of acid metabolism during strawberry ripening.

An exquisite symbiotic relationship between legumes and rhizobia leads to the development of nitrogen-fixing specialized organs, known as nodules, in nitrate-deficient environments. By contrast, a high level of soil nitrate negatively regulates the pleiotropic phases of root nodule symbiosis (RNS), including rhizobial infection, nodule organogenesis, and leghemoglobin synthesis. Here, we identified a special group of nodule-specific nonsymbiotic leghemoglobin genes (AhLghs) in the crack-entry legume peanut and investigated their functional role and transcriptional regulation. A comparative transcriptomic analysis revealed that the downregulation of nodule inception (AhNIN) and nonsymbiotic leghemoglobin (AhLghs) genes plays a pivotal role in the nitrate-mediated inhibition of RNS in peanut. Knockdown of AhLghs and overexpression of AhLgh1 resulted in lower and higher leghemoglobin content, respectively, corroborating their roles as positive regulators of nitrogen fixation. Knockdown of AhNINs not only inhibited root nodulation but also decreased leghemoglobin content in peanut. Further, DNA-affinity purification sequencing (DAP-seq) analysis identified various nodulation genes, including AhLghs, as targets of AhNINs. Following the validation of DNA-protein interactions via electrophoretic mobility shift assay, transactivation assays revealed that AhNINs positively regulate AhLgh1 after binding to the NIN RESPONSIVE CIS ELEMENT (NRCE) of its promoter. Our work bridges a critical gap in understanding how nitrate influences nonsymbiotic leghemoglobin expression by targeting rhizobia-induced NINs in peanut and offers a potential model suggesting that the nitrate-NIN-Lgh module might represent a key evolutionary event in fine-tuning root nodulation.

Hyperglycemia and elevated saturated free fatty acids are key metabolic stressors implicated in vascular injury. However, the early transcriptional responses of endothelial cells to combined glucose and lipid stress remain incompletely defined. This exploratory in vitro study investigated whether high-glucose conditioning modifies palmitate-associated oxidative and endothelial stress-related gene expression responses in human umbilical vein endothelial cells (HUVECs).

Methyl-CpG-binding domain protein 2 (MBD2) is a key epigenetic regulator implicated in tumorigenesis by repressing tumor suppressor genes by recognizing DNA methylation marks and recruiting specific histone-modifying enzymes and chromatin remodeling complexes. Although KCC-07 has been identified as a potent selective MBD2 inhibitor, its cytotoxic effects on various cancer cells remain largely unexplored. In the current study, we have examined the anti-proliferative and cytotoxic activities of KCC-07 on breast cancer (MCF-7), prostate cancer (PC-3), hepatocellular carcinoma (Huh-7), and osteosarcoma (U2-OS) cell lines, along with human skin fibroblasts (HFF-1) as a non-malignant control.

Polycystic ovarian syndrome (PCOS) is a prevalent metabolic and neuroendocrine disease affecting females of childbearing age. Irregular ovulation, elevated androgen levels, and the presence of multiple ovarian cysts characterize it. This study aimed to investigate the prolonged impact of RA on female fertility during three oestrus cycles, utilizing biochemical, histopathological, and immunohistochemical analyses. Twelve female mice were classified into two groups of 6 animals each: (1) the negative control group that received DMSO diluted with sunflower oil, and (2) the positive control group that received a 10 mg/kg dose of retinoic acid. For 15 days, intraperitoneal injections were given daily. The animals were physically euthanized by slaughter on day 16 after treatment. Histopathological and immunohistochemical expression of EGFR, as well as hormonal level investigations, including FSH and LH, were performed on day 16. A 10 mg/kg RA daily dose for 15 days significantly induces FSH and reduces LH. In addition, we revealed that exogenous excess RA leads to PCOS, which causes an increase in cystic follicles and a reduction in antral follicles and corpus luteum. Immunohistochemically, excessive RA suppresses the expression of EGFR, which is localized in granulosa cells. Our investigation concluded that inhibition of epidermal growth factor receptor (EGFR) signaling resulting from long-term high-dose treatment with retinoic acid (RA) affects cumulus granulosa cell proliferation and oocyte maturation. So, vitamin A may harm female fertility.