Cell and Bioscience最新文献

Background: Loss of tumor suppressor Krüpple-like factor 4 (KLF4) expression in hepatocellular carcinoma (HCC) is crucial for aggressive tumor progression and poor patient prognosis. However, the mechanisms underlying KLF4 loss in human HCC are poorly characterized. Here, we explore the mechanisms by which canonical TGF-β1 signaling suppresses KLF4 in HCC.

Methods: The expression and correlation of KLF4, FAT10 and phospho-SMAD2/3 (pSMAD2/3) were evaluated by using tissue microarray and immunohistochemistry. Cellular and molecular impacts of TGF-β1 signaling on FAT10 and KLF4 expression as well as the interaction between FAT10 and KLF4 were determined using western blot, quantitative real-time PCR, chromatin immunoprecipitation, reporter promoter assay, co-immunoprecipitation and immunofluorescence.

Results: We found that elevated p-SMAD2 and p-SMAD3 expression correlated with increased FAT10 but decreased KLF4 expression in primary HCC. High p-SMAD2 and p-SMAD3 expression also associated with reduced overall and recurrence-free survival after surgery in HCC. Activation of TGF-β1 signaling in HCC cells transcriptionally upregulated FAT10, but downregulated KLF4 expression. Mechanistically, activation of TGF-β1 signaling enhanced the direct binding of SMAD2/3 to FAT10 and KLF4 promoter. Furthermore, FAT10 directly interacted with KLF4 protein, and deletion of the C-terminal diglycine motif of FAT10 or the Zinc-finger domain of KLF4 abrogated the interaction. Moreover, FAT10 promoted KLF4 proteasomal degradation in a ubiquitin-independent manner in HCC cells.

Conclusions: Our data suggest that active TGF-β1/SMAD signaling contributes to the loss of KLF4 expression in human HCC through FAT10-mediated ubiquitin-independent proteasomal degradation and direct transcriptional suppression.

Japanese encephalitis virus (JEV), a neurotropic flavivirus, poses a significant public health threat, yet the molecular mechanisms underlying its interaction with host immunity remain poorly understood. This study reveals that zinc finger protein ZNF33B promotes JEV replication by subverting the RLR-mediated innate immune response through orchestrating m⁶A RNA modification. ZNF33B directly binds to antiviral transcripts Ifih1 (encoding MDA5), Mavs, and Irf3, recruiting the m⁶A methyltransferase METTL14 to enhance their m⁶A methylation. Concurrently, ZNF33B interacts with the nuclear m⁶A reader YTHDC1 to facilitate the export of these methylated transcripts from the nucleus to the cytoplasm. In the cytoplasm, the m⁶A-modified transcripts are recognized by the cytoplasmic reader YTHDF2, leading to accelerated RNA decay. This process downregulates MDA5 and IRF3 protein levels, suppressing type I interferon production and downstream antiviral responses, thereby creating a permissive environment for JEV replication. Our findings establish a regulatory axis where ZNF33B integrates m⁶A modification and RNA metabolism to evade host immunity, highlighting the potential of targeting epitranscriptomic pathways for antiviral therapy.

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with epileptic seizures caused by genetic mutations in either TSC1 or TSC2 gene. Multiple genetic, epigenetic, and environmental factors can affect the phenotypical outcomes of TSC individuals. Accumulating evidence has shown that the seizures occurred in early life may contribute to the epileptogenesis and aggravate the neurological setting and neuropsychiatric symptoms of TSC. Therefore, treatments targeting seizures and/or epileptogenesis have always been the main focus on TSC therapies. Current anti-epileptic drugs and mTOR inhibitors show some efficacy, yet up to one-third of TSC-epileptic individuals are classified as refractory epilepsy. Vigabatrin, which has been used as the first-line therapy for infantile spasms in TSC, has demonstrated to delay the onset and lower the overall incidence of seizures in infants with TSC when it was used as a preventive treatment. Recently, because of its efficacy, cannabidiol, which targets adenosine signaling pathway, has been approved by the U.S. FDA for the treatment of TSC-associated epilepsy, suggesting an anti-epilepsy strategy other than mTOR inhibition is also plausible for TSC. To this end, we sought for a preventative treatment of an adenosine pathway-targeted therapeutic strategy. In this study, we pretreated Tsc2^+/- mice with J4, an equilibrative nucleoside transporter 1 inhibitor, before the initiation of kindling epileptogenesis driven by the repetitive PTZ induction paradigm. We found that J4 reduced the seizure behavior severity in Tsc2^+/- mice, as well as decreased mossy fiber sprouting resulted from the aberrant neurogenesis upon PTZ injurious insults. We also found that J4 increased the expression of GluR2, inhibited the astrogliosis and microgliosis, and eventually prevented the neuronal cell loss due to the excitotoxicity. The present study provides a new alternative therapeutic concept for pretreating TSC-related epilepsy before the epileptogenesis process.

Chromosomal translocations are prevalent genetic events across multiple pediatric cancers, notably in CNS tumors, solid tumors, and leukemias. For decades, Fusion oncoproteins resulting from chromosomal translocations have been proposed as a hallmark of cancers, some of which can drive the process of cancers as the initial event of the disease. In addition, studies have shown that some tumor cells become addicted to the activity of fusion proteins, and cell death occurs when the fusion proteins are depleted. These researches suggest that fusion oncoproteins are one of the most promising targets for cancer treatment. Although fusion proteins are already recognized as critical oncogenic drivers, increasing evidence suggests that they can also form positive feedback loops with other proteins. In cancer patients, positive feedback loops have been shown to activate various oncogenic signals to drive tumor development, and influencing tumor cells' sensitivity to different therapies. Therefore, these loops not only amplify the functions of the fusion proteins but also render single-agent targeting of the fusion protein insufficient to suppress tumor growth, highlighting the therapeutic potential of combination strategies in treating fusion-positive tumors. This review highlights the oncogenic roles of fusion protein-driven positive feedback loops in tumor initiation and progression, outline the molecular mechanisms underlying their formation and function, and summarize emerging therapeutic strategies targeting these circuits, offering new insights into the treatment of fusion-positive cancers.

Liver fibrosis/cirrhosis, characterized by excessive deposition of extracellular matrix (ECM) and formation of fibrous scars, arises from chronic liver injury and poses a significant global health burden. Although liver transplantation remains the sole curative option, its application is limited by donor scarcity, immune rejection risks, and high costs. Cellular therapies, particularly those based on mesenchymal stromal cells (MSCs), have emerged as a promising alternative. This review comprehensively examines the therapeutic mechanisms and clinical efficacy of diverse cell therapies for liver cirrhosis, with a focus on MSC-based approaches. MSCs demonstrate multifaceted advantages, including immunomodulatory properties, anti-fibrotic effects (via hepatic stellate cell inhibition and ECM remodeling), promotion of hepatocyte regeneration, and mitigation of oxidative stress. Their low immunogenicity facilitates allogeneic transplantation, while their availability from multiple sources (e.g., bone marrow, umbilical cord, adipose tissue) supports scalable clinical application. We analyze 95 registered clinical trials (73 MSC-focused), highlighting consistent safety profiles but variable efficacy, influenced by factors such as cell source, preparation protocols, administration route, and patient heterogeneity. Key challenges include standardizing MSC production (donor selection, culture conditions, cryopreservation), optimizing delivery methods (intravenous vs. intrahepatic routes), and defining dosing regimens. Strategies to enhance MSC efficacy-such as genetic modification, biomaterial engineering, combinatorial therapies (e.g., with endothelial progenitor cells or macrophages), and MSC-derived extracellular vesicles-are critically evaluated. Future perspectives emphasize the need for large-scale randomized trials, single-cell technologies to resolve MSC heterogeneity, and organoid models to refine therapeutic protocols.

Background: Cancer is a leading cause of mortality worldwide, necessitating the development of novel therapeutic targets and strategies to prevent recurrence and metastasis. In this study, we aimed to evaluate whether a recombinant attenuated Salmonella vaccine (RASV) can stimulate antitumor immunity and prevent cancer progression in vivo.

Methods: We established a mouse model by transplanting cancer cells subcutaneously 4 weeks after oral RASV inoculation and analyzed bone marrow (BM) cells and tumor-infiltrated immune cells by flow cytometry. Further, we established a 4 T-1-induced metastatic cancer model to evaluate the RASV-mediated prevention of tumor metastasis.

Results: Adjuvant RASV significantly reduced tumor growth by enhancing CD8⁺ T cell activity and inducing changes in BM progenitor cells, which contributed combinatorically to the antitumor effects of RASV by increasing the number of common lymphoid progenitor cells. The antitumor effects mediated by RASV were inhibited upon interleukin (IL)-7 receptor blockage. Moreover, interferon-γ-stimulated genes, including Irf1, were upregulated in the BM of RASV-treated mice, thus mediating IL-7 expression. Furthermore, RASV inoculation prevented lung metastasis in mice with breast cancer.

Conclusions: RASV inoculation can promote marked alterations in the BM microenvironment, thus reshaping the anticancer immune response in vivo. This strategy holds therapeutic potential for preventing cancer recurrence and metastasis.

ZMIZ2, a transcription co-activator, is frequently overexpressed in various tumors. However, its functional role and molecular mechanisms in driving non-small cell lung cancer (NSCLC) metastasis remain elusive. Our study reveals that ZMIZ2 is significantly overexpressed in lung adenocarcinoma (LUAD) tissues and is strongly correlated with adverse patient outcomes. Elevated ZMIZ2 expression enhances LUAD cell proliferation, migration, invasion and metastasis, whereas ZMIZ2 depletion exerts opposing effects. Mechanistically, ZMIZ2 physically interacts with PIN1 to trigger K63-linked ubiquitination-dependent PIN1 stabilization, which consequently hyperactivates the PI3K/AKT signaling axis. Notably, silencing PIN1 expression significantly attenuated ZMIZ2-mediated activation of the PI3K/AKT signaling pathway and inhibited LUAD cell proliferation, migration and invasion. Collectively, our findings establish ZMIZ2 as a novel metastasis driver that orchestrates LUAD progression through PIN1-mediated PI3K/AKT pathway activation, providing a rationale for targeting this axis in precision oncology.

Background: Trophoblast cells are a critical component of retained products of conception (RPOC). While mifepristone is widely used as a non-invasive treatment for RPOC, its precise molecular mechanisms in trophoblast regulation remain poorly defined.

Results: Through integrated in vitro and in vivo approaches using human trophoblast stem cells (TSCs), HTR8/SVneo cells, and placental villus explants, we demonstrated that mifepristone exerts its effects predominantly via progesterone receptor (PGR) antagonism rather than glucocorticoid receptor (GR) inhibition. PGR knockdown in TSCs and trophoblast organoids impaired trophoblast stemness. RNA-sequencing of PGR-knockdown TSCs revealed upregulated apoptosis and reduced self-renewal and differentiation abilility, identifying PDCD4 as a key downstream target. Functional experiments showed that PDCD4 overexpression recapitulated the mifepristone-induced trophoblast dysfunction, including diminished proliferation, migration, invasion, and stemness, as well as increased apoptosis. In vivo, mifepristone administration in pregnant mice elevated PDCD4 expression, enhanced placental apoptosis, and facilitated clearance of conception products.

Conclusions: Our findings reveal that mifepristone impairs trophoblast function by antagonizing PGR and inducing PDCD4, thereby impairing stemness and promoting apoptosis. This mechanistic insight not only advances our understanding of mifepristone's action in RPOC treatment but also suggests broader clinical implications for targeting trophoblast function.

Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a crucial coactivator that regulates mitochondrial biogenesis and function across diverse tissues, including the brain, heart, skeletal muscle, bone marrow, and liver. The diversity of PGC-1α isoforms in distinct tissues allows this co-transcription factor to exert wide-ranging biological effects, including regulating mitochondrial functions, oxidative stress, and endoplasmic reticulum homeostasis. Here, we focus on the key roles of PGC-1α in cell differentiation. Initially identified in brown adipose tissue in response to cold exposure, PGC-1α regulates cell differentiation by modulating gene expression networks involved in mitochondrial biogenesis. PGC-1α influences cell fate in several cell types, including adipocytes, skeletal muscle cells, and bone marrow-derived cells. A deeper understanding of PGC-1α provides valuable insights into developmental biology, tissue formation, and potential therapeutic targets for regenerative medicine and disease treatment. This review explores recent progress in understanding the roles of PGC-1α in cell differentiation, offering an integrated perspective on its significance in tissue and organism development.

Backgrounds: Recent research has emphasized the significance of testis-specific serine proteases in regulating various aspects of sperm maturation and function. Among them, serine protease 55 (PRS55) plays an important role in the energy metabolism of sperm and is essential for male fertility in mice. A recent case study further suggests its potential importance to human fertility. However, the underlying molecular mechanism by which PRS55 influences sperm function are still not well understood. The present study aims to investigate these mechanisms further.

Results: In this study, we found impaired mitochondrial function in Prss55^-/- testes and sperm with low ATP production, and decreased mitochondrial membrane potential in sperm. We then validated that PRSS55 is mainly localized in mitochondria by immunofluorescence staining of sperm and transfected NIH-3T3 cells and immunoblotting of testis and transfected HEK293 cells. In HEK293 cells, overexpression of PRSS55 improved mitochondrial function in vitro, as increased ATP production and NAD+ /NADH ratio. By proteomics, we identified 1593 and 711 differentially expressed proteins (DEPs, fold change > 1.5 and corrected P ≤ 0.05) in PRSS55-enriched testicular cells and sperm between wt and Prss55^-/- mice, respectively. Functional annotation revealed that these DEPs were mainly associated with energy metabolic pathways, especially branched-chain amino acid (BCAA) metabolism and oxidative phosphorylation process. In subsequent metabolomic analysis, we observed significant accumulations of BCAAs (valine, leucine and isoleucine) in Prss55^-/- testes. Using LC-MS/MS and Co-IP assays, we discovered and validated that PRSS55 was interacting with two key molecules in BCAA metabolism as branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK) and its substrate mitochondrial branched-chain ketoacid dehydrogenase E1α (BCKDHA).

Conclusions: Our study demonstrates that PRSS55 interacts with BCKDK and BCKDHA, and regulates BCAA metabolism and energy homeostasis, thereby facilitating sperm migration. Our study provides a biological rationale for PRSS55 as a potential therapeutic target for the treatment of male infertility in clinical.