Particulate matter (PM2.5), an environmental pollutant composed of various components, can affect multiple organs. In particular, PM2.5 generated in pig farms contains substances produced in enclosed livestock environments, such as decomposed feed and manure, animal hair, and byproducts of animal activity. However, comprehensive studies investigating the effects of PM2.5 concentration, composition, and metal content on female reproductive function remain limited. In this study, we evaluated the impact of metal components in pig farm-derived PM2.5 on ovarian function and oocyte quality by exposing mice to intratracheal instillation. One week after exposure to metal components (calcium, iron, aluminum, zinc, and lead), ovarian development, apoptosis, and related molecular mechanisms were examined. We investigated their effects on oocyte maturation and developmental competence. The results showed that metal exposure induced ovarian inflammation and apoptosis via the PI3K/AKT signaling pathway. Furthermore, impaired oocyte maturation, spindle abnormalities, abnormal mitochondrial distribution, elevated reactive oxygen species (ROS) levels, and activation of mitochondrial membrane potential (MMP) and TGF-β were observed. In conclusion, our findings indicate that the metal components of PM2.5 from a pig farm can adversely affect ovarian function and oocyte maturation.

Background: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and remains one of the leading contributors to cancer-related mortality worldwide, primarily due to the disease's therapeutic resistance and marked tumor heterogeneity. Among the molecular mechanisms implicated in HCC progression, the dysregulation of the JNK and PI3K/AKT signaling pathways plays a critical role in tumor initiation, cell proliferation, and cell survival. Vemurafenib, a clinically approved inhibitor of mutant BRAF kinase, has shown robust antitumor activity across multiple malignancies. However, its therapeutic utility in HCC remains largely unexplored. Methods: We investigated the anticancer effects of vemurafenib in two human HCC cell lines. Results: Vemurafenib treatments led to significant declines in cell viability and colony formation, accompanied by marked reductions in the migratory and invasive behaviors of HCC cells. Mechanistically, vemurafenib enhanced JNK pathway activation while suppressing AKT phosphorylation. Conclusion: Vemurafenib markedly inhibited HCC cell proliferation and metastasis, which was accompanied by a pronounced induction of apoptosis and G0/G1 phase cell-cycle arrest. At the signaling level, these cellular responses were linked to enhanced JNK activation and the suppression of AKT phosphorylation, suggesting that vemurafenib may serve as a potential therapeutic agent for HCC.

Hepatic inflammation plays a key role in acute and chronic liver diseases by driving hepatocellular injury and promoting disease progression. However, the molecular mechanisms that maintain hepatic immune homeostasis remain unclear. Cathepsin A (Ctsa), a lysosomal serine carboxypeptidase involved in protein degradation and enzyme stabilization, has been implicated in lysosomal storage disorders. However, its role in liver immunity is poorly understood. Given the emerging evidence that lysosomal proteases contribute to immune regulation and inflammatory signaling, Ctsa is a promising yet underexplored candidate for elucidating how lysosomal proteases influence hepatic inflammation. To address this gap, this study aimed to investigate Ctsa function using Ctsa knockout (Ctsa-/-) mice. Under basal conditions, Ctsa-/- mice exhibited splenic immune activation and relative hepatomegaly accompanied by histological alterations. Following lipopolysaccharide challenge, the mice developed aggravated liver injury with elevated aminotransferase levels, enhanced immune cell infiltration, and increased pro-inflammatory cytokine expression. These inflammatory changes were accompanied by increased hepatocellular apoptosis, as evidenced by elevated Bax/Bcl-2 ratio, cleaved caspase-3 expression, and increased TUNEL-positive cells. Collectively, these findings indicate that Ctsa contributes to the regulation of hepatic immune and cellular homeostasis, and its loss increases susceptibility to inflammatory liver injury.

Abstract Background Fibroblast-like synoviocytes (FLS) are central mediators of synovial inflammation and joint destruction in rheumatoid arthritis (RA). While tumor necrosis factor-α (TNFα) is known to activate FLS, the upstream regulators that connect inflammatory stimulation with sustained stromal pathogenicity remain poorly defined. The LIN28A‒let-7 microRNA axis regulates proliferation and invasiveness in diverse pathological contexts, but its role in RA FLS remains unclear. Methods LIN28A–let-7b regulation and functional consequences were investigated in TNFα-stimulated MH7A synoviocytes and primary murine FLS. Pathway inhibitor experiments were performed using p38 and NF-κB inhibitors, and pharmacologic modulation of the LIN28–let-7 interaction was evaluated using the small-molecule inhibitor C1632. Expression of LIN28A and let-7b was also examined in synovial tissues from collagen-induced arthritis (CIA) mice. Results TNFα stimulation induced reciprocal regulation of LIN28A and let-7b, with increased LIN28A expression and reduced let-7b levels in MH7A cells and CIA synovial tissues. LIN28A overexpression enhanced proliferation, migration, invasion, and inflammatory mediator production, and increased expression of the let-7 target HMGA2 and matrix-remodeling enzymes. These changes were accompanied by activation of MAPK and NF-κB signaling pathways. Inhibition of p38 or NF-κB attenuated LIN28A-associated inflammatory gene expression. Primary fibroblast-like synoviocytes isolated from Lin28a transgenic mice recapitulated these phenotypes. In addition, disruption of the LIN28–let-7 interaction using C1632 partially restored let-7b expression and suppressed migration, invasion, inflammatory gene expression, and signaling activation. Conclusion LIN28A may act as an upstream regulator of synoviocyte pathogenicity in RA. Targeting the LIN28A‒let-7b axis may represent a therapeutic strategy to modulate stromal contributions to disease progression.

Background Inflammatory Bowel Disease (IBD) represents a chronic and recurrent inflammatory condition affecting the gastrointestinal tract, with a rising global incidence. Current treatment approaches include surgery and drugs. However, surgeries are invasive procedures, while drug treatments often present with various side effects. Gossypetin, a flavonoid found abundantly in plants such as hibiscus, exhibits anti-oxidant and anti-cancer properties. However, its potential impact on IBD remains unexplored.Objective This study aimed to investigate the therapeutic potential of gossypetin on colitis.Methods We employed the DSS-induced colitis model to evaluate the therapeutic potential of gossypetin on colitis. The efficacy of gossypetin was assessed within this model using the Disease Activity Index (DAI) score and histological analysis. Additionally, we utilized qRT-PCR to measure the levels of inflammatory cytokines and Superoxide Dismutase (SOD). Immunohistochemistry confirmed the expression of tight junction markers, COX-2, and phosphorylated JNK protein, normally associated with disease progression. Furthermore, Western blot analysis was conducted to examine the SOD levels and anti-apoptotic effects of gossypetin.Results In DSS-induced colitis mice, gossypetin treatment ameliorated weight loss and reduced colon length caused by DSS treatment. Additionally, gossypetin-treated groups exhibited DAI scores and reduced histological damage. Moreover, gossypetin treatment increased tight junction expression, decreased inflammatory responses, reduced ROS levels, attenuated JNK signaling, and decreased apoptosis.Conclusion Gossypetin shows therapeutic potential for mitigating the symptoms and progression of colitis by targeting ROS-JNK signaling involved in inflammation and tissue damage. This highlights the potential of natural compounds such as gossypetin for targeted therapies with reduced side effects and improved efficacy.

Polystyrene-derived microplastics (PS-MP) are one of the most important environmental problems in modern society and are associated with various chronic disorders. Previous studies have shown that PS-MP exerts estrogenic effects on aquatic organisms. This research indicates that PS-MP may function as an endocrine-disrupting chemical and a risk factor for estrogen-related diseases, such as breast cancer. However, the carcinogenic potential of PS-MPs in breast cancer has not been studied extensively. Therefore, in the present study, we aimed to elucidate the effects of PS-MP on human breast cancer cells. Estrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) human breast cancer cells were exposed to low and high concentrations of PS-MP for 4 weeks. MCF-7 cells exposed to PS-MP exhibited significantly increased cell viability, whereas MDA-MB-231 cells showed no change. Subsequent in vitro and in vivo experiments demonstrated that PS-MP-stimulated MCF-7 cells significantly increased non-genomic ER signaling pathways and tumor growth in mice. Moreover, the ER-knockdown MCF-7 cells were not affected by PS-MP simulation. Our results demonstrate that PS-MP stimulation promotes the malignant transformation of human breast cancer cells via the ER signaling pathway. Considering the emerging concerns regarding PS-MP pollution worldwide, these data provide novel insights into the potential carcinogenic risk of PS-MP to human breast cancer.

Primary cilia are dynamic sensory organelles orchestrating key signaling pathways, and disruption of primary ciliogenesis is implicated in a spectrum of genetic disorders. The peroxisomal bifunctional enzyme HSD17B4 is pivotal for peroxisomal β-oxidation and acetyl-CoA synthesis, and its deficiency profoundly impairs peroxisomal metabolism. While patients with HSD17B4 deficiency exhibit ciliopathy-like symptoms due to dysfunctional primary cilia, the molecular connection between HSD17B4 and ciliopathy remains poorly understood. Here, we demonstrate that HSD17B4 deficiency impairs primary ciliogenesis and alters cilia-mediated signaling, suggesting a potential link between peroxisomal metabolism and ciliary function. Notably, elevation of acetyl-CoA rescues ciliary defects via HDAC6-mediated ciliogenesis in HSD17B4-deficient cells. Strikingly, acetate administration restores motor function, enhances primary cilia formation, and preserves the Purkinje layer in Hsd17B4-knockout mice. These findings provide insights into the functional link between HSD17B4 and primary cilia, highlighting acetyl-CoA as a potential therapeutic target for HSD17B4 deficiency and ciliopathy. HSD17B4 deficiency disrupts peroxisomal metabolism and causes ciliopathy-like phenotypes. Here the authors show that acetyl-CoA restores primary cilia and improves cerebellar defects in Hsd17B4-deficient models, suggesting a potential therapeutic strategy.

BACKGROUND/AIM:Pre-mRNA processing factor 4 (PRPF4), a core protein of U4/U6 small nuclear ribonucleoproteins (snRNPs), is crucial for maintaining their structure by interacting with PRPF3 and Cyclophilin H. Beyond its role in splicing, PRPF4 has been implicated in cell survival, apoptosis, and oncogenesis. Although PRPF4 mutations have been associated with retinitis pigmentosa, its role in glioblastoma (GBM) remains unclear. This study aimed to investigate the function of PRPF4 in GBM progression and its potential as a therapeutic target. MATERIALS AND METHODS:Gene expression profiling was conducted to compare PRPF4 levels between GBM tumors and normal tissues. PRPF4 expression was also evaluated in various cancer and GBM cell lines. Stable PRPF4 knockdown cell lines were established using A172 and T98G GBM cell lines. Cellular proliferation, apoptosis, migration, and invasion were assessed through gene expression and functional assays. Additionally, molecular pathways affected by PRPF4 knockdown were examined, focusing on the p38 MAPK signaling pathway. Finally, metabolic processes in PRPF4 knockdown cells were estimated through proteomic analysis. RESULTS:PRPF4 expression was elevated in GBM. Knockdown of PRPF4 reduced cell proliferation, induced apoptosis, and suppressed migration and invasion in GBM cells. PRPF4 knockdown also suppressed MKK3/6-p38-ATF2 and RAS-MEK-ERK1/2 signaling pathways. Proteome analysis revealed disruptions in metabolic pathways, including glutathione and carbon metabolisms, which are associated with GBM progression. CONCLUSION:PRPF4 knockdown inhibits GBM progression by reducing p38 MAPK and ERK signaling cascade with metabolic alterations. Targeting PRPF4 may offer novel therapeutic strategies for GBM treatment.

Esophageal squamous cell carcinoma (ESCC), one of the most frequent malignant tumors of the digestive system, is marked by a poor prognosis and high mortality rate. There is a critical need for effective therapeutic strategies with minimal side effects. Isoquercitrin (IQ) is a natural compound with potent antioxidant properties in cancer and cardiovascular diseases. However, its specific effects and mechanisms in ESCC remain largely unexplored. This study aims to investigate the effects of IQ in ESCC cells and elucidate the mechanisms underlying its therapeutic effects. Specifically, its impact on cell proliferation, colony formation, migration, and invasion was assessed using cell viability assay, morphology, transwell, and colony formation assays. The effects on apoptosis were evaluated by flow cytometry, while immunofluorescence (IF) staining and Western blotting were performed to confirm the underlying mechanisms. The in vivo anti-cancer effects of IQ were then evaluated using a xenograft tumor model. Our results demonstrate that IQ inhibits ESCC cell growth and colony formation while promoting its apoptosis by enhancing caspase activation and downregulating Bcl-2 expression. Furthermore, IQ suppresses cell migration by modulating the epithelial-mesenchymal transition-related proteins. Additionally, IQ induces excessive autophagy by promoting reactive oxygen species accumulation and inhibiting the AKT/mTOR signaling pathway. Importantly, IQ effectively reduces tumor growth in vivo, highlighting its potential as a therapeutic agent for ESCC.

Parkinson's disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer's disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (Hspa9 +/-) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, Hspa9 haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Hspa9 +/- mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.

This study aimed to identify the effects of major metal components present in particulate matter (PM)2.5 on the reproductive system, sperm function, and embryo development. Through intratracheal instillation, male mice were exposed to various concentrations of metal components, including calcium oxide (Ca), iron oxide (Fe), aluminum oxide (Al), zinc oxide (Zn), lead oxide (Pb), and a mixture of these metals, in PM2.5 collected from the porcine farm. After 14 days, testicular inflammation and abnormal sperm morphology were observed in the exposed mice. These results indicate that such metal exposure enhances inflammatory cytokines in the testis and oxidative stress-induced apoptosis. Moreover, the exposure influenced sperm deformation, capacitation status, testosterone levels, and testosterone biosynthesis. Importantly, embryo development was also found to be impacted due to decreased sperm fertility. This study demonstrates that major metal components of PM2.5 derived from porcine farm pose adverse effects on the male reproductive system.

BACKGROUND/AIM:Skin wound healing is a physiological process restoring the structural and functional integrity of injured skin. During this process, wound management preventing bacterial infection and complications is important for the regeneration of skin layers and adnexa, as well as the protective function of the skin. Therefore, the development of an effective ointment to promote wound healing without complications is beneficial. MATERIALS AND METHODS:This study developed Raepenol™ cream, comprising a base cream and natural compounds including paeonol, D-panthenol and extract of Centella asiatica, and assessed its therapeutic effect in wound healing. A rat model of skin wound healing and a mouse model of imiquimod-induced pruritus were employed. The effect of Raepenol™ cream was evaluated by wound size and histological analysis, including the integrity of skin structures and inflammatory response. RESULTS:Raepenol™ cream treatment effectively restored the structural integrity of the skin in rats, including wound closure, regeneration of skin adnexa, and reconstitution of collagen, comparable to commercial ointment. Additionally, Raepenol™ cream significantly suppressed pruritus by inhibiting mast cell infiltration or retention in the inflammatory site of mouse ears. CONCLUSION:Raepenol™ cream effectively promoted wound healing and relieved pruritus in animal models. These results suggest that it could be a promising option for wound care and pruritus relief, offering potential advantages over current ointments.

BACKGROUND/AIM:Silibinin, has been investigated for its potential benefits and mechanisms in addressing vanadium pentoxide (V2O5)-induced pulmonary inflammation. This study explored the anti-inflammatory activity of silibinin and elucidate the mechanisms by which it operates in a mouse model of vanadium-induced lung injury. MATERIALS AND METHODS:Eight-week-old male BALB/c mice were exposed to V2O5 to induce lung injury. Mice were pretreated with silibinin at doses of 50 mg/kg and 100 mg/kg. Histological analyses were performed to assess cell viability and infiltration of inflammatory cells. The expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and activation of the MAPK and NF-[Formula: see text]B signaling pathways, as well as the NLRP3 inflammasome, were evaluated using real-time PCR, western blot analysis, and immunohistochemistry. Whole blood analysis was conducted to measure white blood cell counts. RESULTS:Silibinin treatment significantly improved cell viability, reduced inflammatory cell infiltration, and decreased the expression of pro-inflammatory cytokines in V2O5-induced lung injury. It also notably suppressed the activation of the MAPK and NF-[Formula: see text]B signaling pathways, along with a marked reduction in NLRP3 inflammasome expression levels in lung tissues. Additionally, silibinin-treated groups exhibited a significant decrease in white blood cell counts, including neutrophils, lymphocytes, and eosinophils. CONCLUSION:These findings underscore the potent anti-inflammatory effects of silibinin in mice with V2O5-induced lung inflammation, highlighting its therapeutic potential. The study not only confirms the efficacy of silibinin in mitigating inflammatory responses but also provides a foundational understanding of its role in modulating key inflammatory pathways, paving the way for future therapeutic strategies against pulmonary inflammation induced by environmental pollutants.

Industrialization and urbanization produce hazardous particulate matter (PM), including ammonium compounds like (NH4)2SO4 4 ) 2 SO 4 and NH4NO3, 4 NO 3 , which comprise around 50 % of PM. Despite this, the influence of ammonium on intestinal inflammation remains unclear. We studied an ammonium mixture's effects on the intestine, finding elevated pro-inflammatory cytokines and oxidative stress in exposed mice, causing small intestine morphological changes. Investigating mitigation strategies, we assessed silibinin, an antioxidant from milk thistle seeds. Silibinin treatment in (NH4)2SO4- 4 ) 2 SO 4- and NH4NO3-exposed 4 NO 3-exposed mice significantly reduced inflammatory markers, alleviated oxidative stress, and preserved intestinal tissue integrity via the PI3K/AKT pathway. Our findings elucidate ammonium's potential impact on intestinal inflammation and highlight silibinin's therapeutic impact against PM-induced small intestine damage.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that is influenced by various factors, including environmental factors, immune responses, and genetic elements. Among the factors that influence IBD progression, macrophages play a significant role in generating inflammatory mediators, and an increase in the number of activated macrophages contributes to cellular damage, thereby exacerbating the overall inflammatory conditions. HSPA9, a member of the heat shock protein 70 family, plays a crucial role in regulating mitochondrial processes and responding to oxidative stress. HSPA9 deficiency disrupts mitochondrial dynamics, increasing mitochondrial fission and the production of reactive oxygen species. Based on the known functions of HSPA9, we considered the possibility that HSPA9 reduction may contribute to the exacerbation of colitis and investigated its relevance. In a dextran sodium sulfate-induced colitis mouse model, the downregulated HSPA9 exacerbates colitis symptoms, including increased immune cell infiltration, elevated proinflammatory cytokines, decreased tight junctions, and altered macrophage polarization. Moreover, along with the increased mitochondrial fission, we found that the reduction in HSPA9 significantly affected the superoxide dismutase 1 levels and contributed to cellular death. These findings enhance our understanding of the intricate mechanisms underlying colitis and contribute to the development of novel therapeutic approaches for this challenging condition.

Glucose-dependent insulinotropic polypeptide (GIP), a 42-amino- acid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging.

Oral squamous cell carcinoma (OSCC) is a prevalent oral and maxillofacial cancer with high mortality as OSCC cells readily invade tissues and metastasize to cervical lymph nodes. Although imatinib exhibits potential anticancer and remarkable clinical activities that therapeutically affect several cancer types, its specific impact on OSCC has yet to be fully explored. Therefore, this study investigated the potential anticancer effect of imatinib on OSCC cells and the underlying mechanisms. The Cell Counting Kit-8 was used to determine the impact of imatinib on cell viability. Then, morphological cell proliferation analysis was conducted to examine how imatinib impacted OSCC cell growth. Moreover, OSCC cell migration was determined through wound-healing assays, and colony formation abilities were investigated through the soft agar assay. Lastly, the effect of imatinib on OSCC cell apoptosis was verified with flow cytometry, and its inhibitory mechanism was confirmed through Western blot. Our results demonstrate that imatinib effectively inhibited OSCC cell proliferation and significantly curtailed OSCC cell viability in a time- and concentration-dependent manner. Furthermore, imatinib suppressed migration and colony formation while promoting OSCC cell apoptosis by enhancing p53, Bax, and PARP expression levels and reducing Bcl-2 expression. Imatinib also inhibited the PI3K/AKT/mTOR signaling pathway and induced OSCC cell apoptosis, demonstrating the potential of imatinib as a treatment for oral cancer.

Background/Aim: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses and a multifactorial etiology. While imatinib has demonstrated efficacy in the treatment of immune-related diseases, its potential effects in IBD treatment remain underexplored. Materials and Methods: This study aimed to investigate the therapeutic effects of imatinib in colitis treatment. A dextran sulfate sodium (DSS)-induced colitis model was used to mimic IBD in mice. Imatinib was administered orally to mice simultaneously with DSS treatment. The effects of imatinib on DSS-induced colitis were evaluated by analyzing colitis-related pathology, including the disease activity index (DAI), histological lesions, inflammatory markers, and tight junction integrity. Additionally, western blot analysis and quantitative real-time polymerase chain reaction were used to assess inflammatory markers, tight-junction proteins, and cell death. Results: In the DSS-induced colitis model, imatinib treatment exerted protective effects by attenuating weight loss, restoring colon length, reducing spleen weight, and improving the DAI score and histological lesions. Additionally, imatinib reduced the level of proinflammatory cytokines, including TNF alpha , IL-6, and IL-1 beta. beta . Furthermore, imatinib treatment restored tight-junction integrity and decreased the expression of apoptosis marker proteins. Conclusion: Overall, imatinib treatment significantly alleviated the symptoms of DSS-induced colitis by influencing the expression of proinflammatory cytokines, tight junction proteins, and apoptotic markers in mice. These findings highlight imatinib as a potential therapeutic candidate for IBD.

Fine particulate matter (PM) 2.5 contains metals, ions, and carbon compounds, varying dynamically due to environmental factors. This study identified five major metals (Ca, Fe, Al, Zn and Pb) in urban PM2.5 via meta-analysis and evaluated their hazardous effects on health. Mice were exposed to these metals through intratracheal instillation, revealing changes in white blood cell count and serum substances (bilirubin, BUN and LDH), along with lung inflammation. Increased levels of proinflammatory cytokines (IL-1b, IL-6 and TNF-alpha) were observed, indicating adverse effects on the respiratory system. These results suggest that further studies on the health effects of the major metals of PM2.5, development of indicators for determining the PM2.5 exposure levels, and methods for reducing the metals together with other components in PM2.5 are needed.

Background/Aim: Human melanoma-associated antigen A2 (hMAGEA2) family members play several roles in many types of cancer and have been explored as potential prognostic markers. In this study, we investigated the molecular mechanism underlying hMAGEA2-mediated tumorigenesis of prostate cancer. Materials and Methods: Immunohistochemistry and western blot were used to assess protein expression whereas microarray and quantitative reverse transcription–PCR determined mRNA expression. CCK-8 assay was used to determine cell proliferation. Colony formation assay was used to examine tumorigenesis. Migration and invasion were examined using a transwell assay. Propidium iodide (PI)/Annexin V double staining was performed to measure apoptosis. Transcriptional activity was measured using Dual-luciferase reporter assay. Results: hMAGEA2 was highly over-expressed in human prostate cancer tissues compared to benign prostatic hyperplasia tissues. To elucidate its biological function in prostate cancer, we established two stable hMAGEA2-knockdown prostate cancer cell lines, PC3M and 22RV1, and found that they presented significantly decreased proliferation, anchorage-independent colony formation, migration, and invasion. As hMAGEA2 knockdown suppressed prostate cancer cell growth, we examined its potential influence on tumor apoptosis. hMAGEA2-knockdown cell lines displayed early apoptosis. Moreover, knockdown of hMAGEA2 resulted in the down-regulation of EFNA3 expression. Luciferase assay showed that hMAGEA2 bound to the EFNA promoter region and regulated its transcription. Down-regulation of EFNA3 expression led to decreased Ras/Braf/MEK/Erk1/2 phosphorylation and, consequently, inhibited prostate cancer progression. Conclusion: hMAGEA2 promotes prostate cancer growth, metastasis, and tumorigenesis by regulating the EFNA3–Erk1/2 signaling pathway, indicating its potential as a therapeutic marker for prostate cancer.