Results of previous studies suggested that programmed cell death 4 (PDCD4) was overexpressed in cerebral ischemia (CI), and mothers against decapentaplegic homolog 1 (SMAD1) is a transcription factor of PDCD4, and it is also elevated in CI; however, the regulatory mechanism of SMAD1/PDCD4 axis in CI remains unclear. The current work has been designed to explore the role and associated mechanisms of SMAD1/PDCD4 in CI. PDCD4 and SMAD1 expressions have been examined by real-time reverse transcription-polymerase chain reaction (RT-qPCR) method, and receiver operating characteristic (ROC) curve analysis has been performed to determine the potential diagnostic value of PDCD4 and SMAD1. An oxygen-glucose deprivation (OGD) model has been used to investigate the effects of PDCD4 and SMAD1 on CI in vitro. Cell apoptosis was evaluated using TdT-mediated dUTP nick end labeling (TUNEL) assays. The interaction between SMAD1 and PDCD4 axis has been confirmed by using dual-luciferase reporter as well as chromatin immunoprecipitation (Ch-IP) assays. Finally, the effects of SMAD1/PDCD4 axis on the ferroptosis of neuron cells have been examined. PDCD4 was overexpressed in blood samples of CI patients. ROC analysis showed the AUC for PDCD4 was 0.7478, and NIHSS and MRS scores were positively correlated with PDCD4 expression. Moreover, the cellular OGD model was established and knockdown of PDCD4 suppressed the apoptosis of neurons. Besides, knockdown of PDCD4 also inhibited ferroptosis of OGD-treated neuron cells in vitro. Additionally, SMAD1 was upregulated in blood samples of CI patients, NIHSS and MRS scores were positively correlated with SMAD1 expression, and SMAD1 is a transcriptional factor of PDCD4, and SMAD1 could transcriptionally regulate the expression of PDCD4. Finally, SMAD1 could regulate the ferroptosis of neuron cells through regulating the transcription of PDCD4. The SMAD1/PDCD4 axis regulates the growth, apoptosis, and ferroptosis of neuron cells, suggesting that targeting the SMAD1/PDCD4 axis may be a potential therapeutic method.

Programmed cell death protein 4 (PDCD4) is instrumental in regulating a range of cellular processes such as translation, apoptosis, signal transduction, and inflammatory responses. There is a notable inverse correlation between PDCD4 and the mammalian target of rapamycin (mTOR) pathway, which is integral to cellular growth control. Activation of mTOR is associated with the degradation of PDCD4. Although the role of PDCD4 is well established in oncogenesis and immune response regulation, its function in mycobacterial infections and its interplay with the mTOR pathway necessitate further elucidation. This study investigates the modulation of PDCD4 expression in the context of mycobacterial infections, revealing a consistent pattern of downregulation across diverse mycobacterial species. This observation underscores the potential utility of PDCD4 as a biomarker for assessing mTOR pathway activation during such infections. Building on this finding, we employed a novel approach using PDCD4-based mTOR (Tor)-signal-indicator (TOSI) reporter cells for the high-throughput screening of FDA-approved drugs, focusing on mTOR inhibitors. This methodology facilitated the identification of several agents, inclusive of known mTOR inhibitors, which upregulated PDCD4 expression and concurrently exhibited efficacy in impeding mycobacterial proliferation within macrophages. These results not only reinforce the significance of PDCD4 as a pivotal marker in the understanding of infectious diseases, particularly mycobacterial infections, but also illuminate its potential in the identification of mTOR inhibitors, thereby contributing to the advancement of therapeutic strategies.
OBJECTIVE: This study emphasizes the critical role of the mammalian target of rapamycin (mTOR) pathway in macrophage responses to mycobacterial infections, elucidating how mycobacteria activate mTOR, resulting in PDCD4 degradation. The utilization of the (Tor)-signal-indicator (TOSI) vector for real-time monitoring of mTOR activity represents a significant advancement in understanding mTOR regulation during mycobacterial infection. These findings deepen our comprehension of mycobacteria\'s innate immune mechanisms and introduce PDCD4 as a novel marker for mTOR activity in infectious diseases. Importantly, this research laid the groundwork for high-throughput screening of mTOR inhibitors using FDA-approved drugs, offering the potential for repurposing treatments against mycobacterial infections. The identification of drugs that inhibit mTOR activation opens new avenues for host-directed therapies, marking a significant step forward in combating tuberculosis and other mycobacterial diseases.

Early life stress (ELS) increases the risk of depression later in life. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases. However, its involvement in a person\'s susceptibility to ELS-related depression is unknown. To examine the effects and underlying mechanisms of PDCD4 on ELS vulnerability, we used a \"two-hit\" stress mouse model: an intraperitoneal injection of lipopolysaccharide (LPS) into neonatal mice was performed on postnatal days 7-9 (P7-P9) and inescapable foot shock (IFS) administration in adolescent was used as a later-life challenge. Our study shows that compared with mice that were only exposed to the LPS or IFS, the \"two-hit\" stress mice developed more severe depression/anxiety-like behaviors and social disability. We detected the levels of PDCD4 in the hippocampus of adolescent mice and found that they were significantly increased in \"two-hit\" stress mice. The results of immunohistochemical staining and Sholl analysis showed that the number of microglia in the hippocampus of \"two-hit\" stress mice significantly increased, with morphological changes, shortened branches, and decreased numbers. However, knocking down PDCD4 can prevent the number and morphological changes of microglia induced by ELS. In addition, we confirmed through the Golgi staining and immunohistochemical staining results that knocking down PDCD4 can ameliorate ELS-induced synaptic plasticity damage. Mechanically, the knockdown of PDCD4 exerts neuroprotective effects, possibly via the mediation of BDNF/AKT/CREB signaling. Combined, these results suggest that PDCD4 may play an important role in the ELS-induced susceptibility to depression and, thus, may become a therapeutic target for depressive disorders.

STAT1 (Signal Transducer and Activator of Transcription 1), belongs to the STAT protein family, essential for cytokine signaling. It has been reported to have either context dependent oncogenic or tumor suppressor roles in different tumors. Earlier, we demonstrated that Glioblastoma multiforme (GBMs) overexpressing FAT1, an atypical cadherin, had poorer outcomes. Overexpressed FAT1 promotes pro-tumorigenic inflammation, migration/invasion by downregulating tumor suppressor gene, PDCD4. Here, we demonstrate that STAT1 is a novel mediator downstream to FAT1, in downregulating PDCD4 in GBMs. In-silico analysis of GBM databases as well as q-PCR analysis in resected GBM tumors showed positive correlation between STAT1 and FAT1 mRNA levels. Kaplan-Meier analysis showed poorer survival of GBM patients having high FAT1 and STAT1 expression. SiRNA-mediated knockdown of FAT1 decreased STAT1 and increased PDCD4 expression in glioblastoma cells (LN229 and U87MG). Knockdown of STAT1 alone resulted in increased PDCD4 expression. In silico analysis of the PDCD4 promoter revealed four putative STAT1 binding sites (Site1-Site4). ChIP assay confirmed the binding of STAT1 to site1. ChIP-PCR revealed decrease in the binding of STAT1 on the PDCD4 promoter after FAT1 knockdown. Site directed mutagenesis of Site1 resulted in increased PDCD4 luciferase activity, substantiating STAT1 mediated PDCD4 inhibition. EMSA confirmed STAT1 binding to the Site 1 sequence. STAT1 knockdown led to decreased expression of pro-inflammatory cytokines and EMT markers, and reduced migration/invasion of GBM cells. This study therefore identifies STAT1 as a novel downstream mediator of FAT1, promoting pro-tumorigenic activity in GBM, by suppressing PDCD4 expression.

The tumor suppressor programmed cell death 4 (PDCD4) is downregulated in various tumor tissues indicating poor prognosis. PDCD4 is the first protein found to resist tumor transformation, invasion, and metastasis by inhibiting translation. The functions of PDCD4 dependent on its structures are affected by extracellular signals. It regulates tumor-related proteins through a variety of mechanisms, especially involved in two major signaling pathways, PI3K-Akt-mTOR and MAPK. By analyzing the relationship between the structures, functions and diseases of PDCD4, this review summarizes the roles of PDCD4 in several physiological processes and diseases such as apoptosis, autophagy, tumor, and inflammation in recent years, thereby providing insights for the study of the signaling pathways of PDCD4 and related proteins and the treatment of diseases targeting them.
程序性细胞死亡蛋白PDCD4(programmed cell death 4)是一种肿瘤抑制蛋白，在多种肿瘤组织中下调并提示不良预后，是第一种被发现通过抑制翻译抵抗肿瘤转化、侵袭和转移的蛋白质。PDCD4自身结构与功能关系密切，并受细胞外信号影响，其蛋白表达水平和功能与人体两大信号通路PI3K-Akt-mTOR和MAPK密切相关，通过多种机制调节与肿瘤相关的其他蛋白质。本文通过解析PDCD4结构、功能与疾病的关系，总结了近年来PDCD4在凋亡、自噬、肿瘤、炎症等生理过程和疾病中的作用，为PDCD4及相关蛋白的信号传导路径研究和以它们为靶标的疾病治疗提供启发和思路。.

This study aimed to investigate the molecular mechanism of the effect of PDCD4 on radiotherapy-induced acute kidney injury (AKI) in rectal cancer through the regulation of FGR/NF-κB signaling. Differentially expressed genes were identified using Gene Expression Omnibus (GEO) datasets (GSE90627 for rectal cancer and GSE145085 for AKI) and R software. The human renal tubular epithelial cell line, HK-2, was used to establish an in vitro model of radiotherapy-induced AKI. RT-qPCR and western blotting were used to detect gene and protein expression levels, respectively. Cell proliferation and apoptosis were assessed using the CCK-8 assay and flow cytometry, respectively. The malondialdehyde and superoxide dismutase levels in the cell culture supernatants were determined. Additionally, an in vivo AKI model was established using BALB/c mice, and kidney tissue morphology, expression of the renal injury molecule KIM-1, apoptosis of renal tubular cells, and TAS and TOS in serum were evaluated. Bioinformatics analysis revealed the upregulated expression of PDCD4 in AKI. In vitro experiments demonstrated that PDCD4 induced apoptosis in renal tubular cells by promoting FGR expression, which activated the NF-κB signaling pathway and triggered an oxidative stress response. In vivo animal experiments confirmed that PDCD4 promoted oxidative stress response and radiotherapy-induced AKI through the activation of the FGR/NF-κB signaling pathway. Silencing PDCD4 attenuated radiotherapy-induced AKI. Our findings suggest that PDCD4 may induce radiotherapy-induced AKI in rectal cancer by promoting FGR expression, activating the NF-κB signaling pathway, and triggering an oxidative stress response.

As obligate parasites, viruses have evolved multiple strategies to evade the host immune defense. Manipulation of the host proteasome system to degrade specific detrimental factors is a common viral countermeasure. To identify host proteins targeted for proteasomal degradation by porcine reproductive and respiratory syndrome virus (PRRSV), we conducted a quantitative proteomics screen of PRRSV-infected Marc-145 cells under the treatment with proteasome inhibitor MG132. The data revealed that the expression levels of programmed cell death 4 (PDCD4) were strongly downregulated by PRRSV and significantly rescued by MG132. Further investigation confirmed that PRRSV infection induced the translocation of PDCD4 from the nucleus to the cytoplasm, and the viral nonstructural protein 9 (Nsp9) promoted PDCD4 proteasomal degradation in the cytoplasm by activating the Akt-mTOR-S6K1 pathway. The C-terminal domain of Nsp9 was responsible for PDCD4 degradation. As for the role of PDCD4 during PRRSV infection, we demonstrated that PDCD4 knockdown favored viral replication, while its overexpression significantly attenuated replication, suggesting that PDCD4 acts as a restriction factor for PRRSV. Mechanistically, we discovered eukaryotic translation initiation factor 4A (eIF4A) was required for PRRSV. PDCD4 interacted with eIF4A through four sites (E249, D253, D414, and D418) within its two MA3 domains, disrupting eIF4A-mediated translation initiation in the 5\'-untranslated region of PRRSV, thereby inhibiting PRRSV infection. Together, our study reveals the antiviral function of PDCD4 and the viral strategy to antagonize PDCD4. These results will contribute to our understanding of the immune evasion strategies employed by PRRSV and offer valuable insights for developing new antiviral targets.IMPORTANCEPorcine reproductive and respiratory syndrome virus (PRRSV) infection results in major economic losses in the global swine industry and is difficult to control effectively. Here, using a quantitative proteomics screen, we identified programmed cell death 4 (PDCD4) as a host protein targeted for proteasomal degradation by PRRSV. We demonstrated that PDCD4 restricts PRRSV replication by interacting with eukaryotic translation initiation factor 4A, which is required for translation initiation in the viral 5\'-untranslated region. Additionally, four sites within two MA3 domains of PDCD4 are identified to be responsible for its antiviral function. Conversely, PRRSV nonstructural protein 9 promotes PDCD4 proteasomal degradation in the cytoplasm by activating the Akt-mTOR-S6K1 pathway, thus weakening the anti-PRRSV function. Our work unveils PDCD4 as a previously unrecognized host restriction factor for PRRSV and reveals that PRRSV develops countermeasures to overcome PDCD4. This will provide new insights into virus-host interactions and the development of new antiviral targets.

OBJECTIVE: Celastrus orbiculatus ethyl acetate extract (COE) is the main extract of the stem of the Chinese herbal C. orbiculatus, which has anti-tumor and anti-inflammatory biological effects. Our previous study showed that COE had a certain reversal effect on the precancerous lesions of gastric cancer (PLGC) in rats, but the exact mechanism of action remains elusive. We aimed to explore the therapeutic effects of COE on PLGC and the potential mechanisms.
METHODS: The PLGC rat model was successfully constructed by N-methyl-N´-nitro-N-nitrosoguanidine (MNNG) multifactorial induction method. Then, COE was prepared to treat the PLGC rat model. Hematoxylin & eosin staining was used to observe gastric mucosal lesions in rats, AB-PAS and HID-AB staining were used to observe intestinal metaplasia. PDCD4-ATG5 signaling pathway was detected by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) in vivo, and autophagy level was detected by IHC, transmission electron microscopy, and RT-PCR in vivo. Besides, the PLGC (MC) cell model was successfully constructed by treating GES-1 cells with MNNG. Then, the morphology, proliferation, and apoptosis of MC cells, and the role of the PDCD4-ATG5 signaling pathway and autophagy in MC cells were evaluated by COE and after the overexpression of PDCD4 treatment.
RESULTS: COE significantly improved gastric mucosal injury and cellular heteromorphism and retarded the progression of PLGC in rats. Further studies indicated COE not only inhibited the level of autophagy but also interfered with the PDCD4-ATG5 signaling pathway in vivo. On the other hand, COE treatment could effectively reverse MC cell damage, inhibit MC cell proliferation, and promote MC cell apoptosis. Furthermore, COE also promoted PDCD4 and inhibited ATG5 expression in vitro, and the inhibitory effect of COE on ATG5-mediated autophagy was further enhanced after the overexpression of PDCD4.
CONCLUSIONS: The study revealed that COE could regulate the PDCD4-ATG5 signaling pathway to inhibit autophagy in gastric epithelial cells, which contributes to reversing the progression of PLGC.

OBJECTIVE: To elucidate the role of programmed cell death factor 4 (PDCD4) in mitochondrial dysfunction caused by sepsis-related vascular endothelial damage.
METHODS: Cultured human umbilical vein endothelial cells (HUVECs) and mouse vascular endothelial cells (C166 cells) were transfected with a small interfering RNA targeting PDCD4 followed by treatment with lipopolysaccharide (LPS) alone or in combination with carbonyl cyanide 3-chlorophenylhydrazone (FCCP). The proteomic changes in the cells after PDCD4 knockdown were analyzed using LC-MS/MS technique. The mRNA expressions of PDCD4 and the genes associated with cell inflammation and apoptosis were detected with RT-PCR, and the expressions of FIS1, DRP1 and OPA1 proteins key to mitochondrial fission and fusion were determined using Western blotting. JC-1 and MitoSOX fluorescent probes were used to observe the changes in mitochondrial membrane potential and mitochondrial reactive oxygen species levels under by a laser confocal microscope.
RESULTS: LPS stimulation of the cells significantly increased the mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP1) and enhanced the cellular expression of PDCD4 (P < 0.05). Proteomic analysis suggested a correlation between PDCD4 knockdown and changes in mitochondrial dynamics in the cells. LPS treatment significantly increased the expressions of mitochondrial fission proteins FIS1 and DRP1 and lowered the expression of the fusion protein OPA1 in the cells (P < 0.05), causing also mitochondrial oxidative stress and reduction of the mitochondrial membrane potential (P < 0.05). In HUVECs, treatment with FCCP significantly attenuated the protective effect of PDCD4 knockdown, which inhibited LPS-induced inflammation and oxidative stress and restored the balance between mitochondrial fission and fusion.
CONCLUSIONS: PDCD4 knockdown protects vascular endothelial cells against LPS-induced damages by repressing mitochondrial fission and oxidative stress, promoting mitochondrial fusion, and maintaining normal mitochondrial function.

To explore the potential mechanism of microRNA (miR)-181b-5p promoting the progression of thyroid cancer (TC) by targeting programmed cell death 4 (PDCD4). Analysis of miR-181b-5p and PDCD4 expression in TC was performed. The impact of miR-181b-5p and PDCD4 on proliferation, migration, invasion, and apoptosis of TC cells was examined. The binding relationship between miR-181b-5p and PDCD4 was predicted and verified. miR-181b-5p was up-regulated in TC, while PDCD4 was down-regulated. Down-regulating miR-181b-5p or up-regulating PDCD4 inhibited the proliferation, migration, and invasion of TC cells, and promoted cell apoptosis. PDCD4 was the downstream target of miR-181b-5p, and down-regulation of PDCD4 counteracted the inhibitory effect of down-regulation of miR-181b-5p on the proliferation, migration, and invasion of TC cells and the promoting effect on apoptosis. miR-181b-5p inhibits the proliferation, migration, and invasion of TC cells and promotes cell apoptosis by targeting PDCD4.