RNA polymerase II (Pol II) is an essential eukaryotic enzyme that transcribes protein‑coding genes and various non‑coding RNAs. RNA polymerase II, I and III subunit L (POLR2L) is a highly conserved component shared by RNA polymerase subunits I, II, and III, which contributes to transcriptional regulation, enzymatic structural integrity, key cellular processes such as proliferation, differentiation, and stress responses. Recent research has shown that POLR2L is not merely a Pol II structural subunit but also plays key roles in disease progression, particularly cancer, where POLR2L dysregulation contributes to tumor growth, metastasis, and resistance to chemotherapy. Additionally, POLR2L is closely linked to major signaling pathways including the PI3K‑Akt, Wnt/β‑catenin, and TGF‑β pathways, highlighting the diverse roles played by POLR2L in cellular signaling. This review summarizes current knowledge on the structural and functional properties of POLR2L, its involvement in various diseases, and its potential as a therapeutic target. By outlining the diagnostic and therapeutic relevance of POLR2L, this review aims to provide a framework for understanding how POLR2L related research may inform transcriptional regulation and its impact on human health and disease.

Glioblastoma (GBM) is a highly aggressive primary central nervous system malignancy characterized by pronounced intratumoral heterogeneity, rapid progression, and resistance to standard therapeutic approaches. Increasing evidence indicates that cathepsin A (CTSA), a lysosomal serine carboxypeptidase with multifunctional roles, is associated with aggressive GBM phenotypes and may contribute to tumor progression through multiple, context-dependent mechanisms. CTSA is an established structural component of the elastin receptor complex (ERC), where it stabilizes NEU1 and supports receptor complex integrity. Whether this scaffolding function facilitates matrikine-mediated signaling relevant to GBM invasion remains to be directly demonstrated. In parallel, CTSA participates in lysosomal regulatory pathways that may influence chaperone-mediated autophagy (CMA), a selective protein degradation process critical for maintaining cellular proteostasis under metabolic and oxidative stress conditions. However, the direct enzymatic action of CTSA on LAMP2A is expected to limit, rather than enhance, CMA activity, indicating that CTSA-high expression cannot be simply equated with CMA-high cellular states. Therefore, the relationships between CTSA expression, LAMP2A turnover, net CMA flux, and immune signaling in GBM remain unresolved. Dysregulation of lysosomal processes may influence protein turnover and stress-adaptive pathways in GBM; however, the specific contribution of CTSA to these processes has not yet been experimentally tested. CTSA-associated lysosomal activity has been linked to the modulation of the tumor immune microenvironment. CTSA-related signatures are associated with increased representation of immunosuppressive myeloid populations, along with reduced effector immune activity, suggesting that CTSA may serve as a marker of immune-suppressed GBM states rather than as a proven causal regulator of immune exclusion. Consistent with this, CTSA-associated changes in lysosomal function may influence immune-related signaling pathways in a context-dependent manner. At the transcriptomic level, CTSA-linked gene expression patterns, including the SLC39A1-CTSA-CLIC1 axis, are associated with mesenchymal-like states and may serve as candidate prognostic indicators in glioma. Thus, CTSA-associated lysosomal pathways provide a hypothesis-generating framework for exploring lysosome-centered vulnerabilities in GBM; although direct functional and translational validation is still needed, CTSA is best interpreted not as a validated oncogenic driver but as a lens for aggressive, mesenchymal-like and myeloid-enriched glioma states and for interpreting lysosome/CMA-associated vulnerabilities.

Pancreatic β-cell function defects are responsible for the pathology of both type 1 and type 2 diabetes. The sensitivity of mTOR Complex 1 (mTORC1) to insulin and nutrients suggests its importance in β-cell function. To assess the effect of mTOR signaling in mouse β-cells, we specifically deleted the mTOR gene in this cellular compartment. These mice display glucose intolerance and do not secrete insulin in response to a glucose challenge. Similarly, depletion of mTOR via siRNA in INS-1 cells demonstrated that the kinase is necessary for glucose-stimulated insulin secretion (GSIS). The effects of mTOR on GSIS were dependent on mTORC1, not mTORC2, and resulted in a selective reduction of NeuroD1 expression, with no impact on PDX1. These findings on NeuroD1 expression were also observed in the islets of diabetic patients. Overall, mTOR signaling regulates insulin secretion and production in β-cells through mTORC1 and NeuroD1.

Background Toxoplasma gondii relies on host cell nutrients, especially glucose, to support its intracellular growth. However, the mechanisms by which it enhances host glucose metabolism remain incompletely understood. Methods We used fluorescence-based glucose uptake assays, flow cytometry, metabolic flux analysis, and gene silencing in ARPE-19 cells, along with transgenic mouse models, to explore how T. gondii manipulates host glucose utilization and whether this promotes parasite proliferation. Results T. gondii infection significantly enhanced host glucose uptake in a dose-dependent manner and promoted GLUT4 translocation to the plasma membrane. Notably, extracellular acidification rate (ECAR) assays demonstrated a marked increase in glycolytic activity following infection. Mechanistically, we identified that the PI3K/AKT signaling pathway mediates the phosphorylation and transcriptional upregulation of TBC1D4, a Rab-GAP protein essential for GLUT4 trafficking. Genetic silencing of TBC1D4 impaired both glucose uptake and parasite replication. Furthermore, we uncovered a regulatory mechanism involving AKT-dependent nuclear signaling that modulates TBC1D4 transcription. In vivo experiments using Phf20 transgenic mice confirmed increased susceptibility to T. gondii and elevated glucose metabolic responses. Conclusions Our study reveals that T. gondii hijacks a host PI3K/AKT-TBC1D4 axis to enhance glucose uptake and glycolysis, thereby ensuring metabolic support for its proliferation. These findings highlight host glucose metabolism as a potential therapeutic target for controlling toxoplasmosis. ### Competing Interest Statement The authors have declared no competing interest.

Endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) is an endoplasmic reticulum (ER)-resident stomatin/prohibitin/flotillin/HflK/C (SPFH) family protein that assembles into oligomeric complexes within detergent-resistant membrane domains. ERLIN1 regulates multiple cellular functions, including protein quality control, calcium signaling, and lipid metabolism. Together with ERLIN2, it forms ER-associated degradation (ERAD) nanodomains through interactions with RING finger protein 170 (RNF170) and transmembrane and ubiquitin-like domain-containing 1 (TMUB1). These specialized domains facilitate the degradation of inositol 1,4,5-trisphosphate receptor type 1 (IP3R) via the ERAD pathway. ERLIN1 also controls cholesterol metabolism by inhibiting sterol regulatory element-binding protein (SREBP) activation and promoting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) degradation. In addition, it blocks cholesterol esterification, thereby enhancing cholesterol transport to the Golgi apparatus. ERLIN1 further regulates cell fate by promoting autophagy and suppressing apoptosis; in complex with ERLIN2, it interacts with activating molecule in Beclin 1-regulated autophagy protein 1 (AMBRA1) at mitochondria-associated membranes to initiate autophagy and binds phosphatidylinositol 3-phosphate to stabilize autophagy signaling. Its overexpression enhances tumor progression, whereas silencing triggers apoptosis in colorectal cancer. Mutations in ERLIN1 are linked to neurodegenerative diseases such as hereditary spastic paraplegia type 62 and atypical amyotrophic lateral sclerosis. The ERLIN1/2 complex also influences immune responses and viral replication through cholesterol regulation. Collectively, these diverse and integrated functions highlight the potential of ERLIN1 as a therapeutic target in cancer, metabolic, neurodegenerative, and infectious diseases.

The mutated in colorectal cancer (MCC) gene is closely associated with the onset and progression of colorectal cancer. MCC plays a critical role in regulating the cell cycle and various signaling pathways and is recognized to inhibit cancer cell proliferation via the β-catenin signaling pathway. β-catenin is a key component of the WNT signaling pathway that influences cell growth, differentiation, survival, and migration, thereby positioning MCC as an important tumor suppressor. Notably, MCC has also been implicated in other cancer types, including lung, liver, and brain cancers. However, the precise mechanisms by which MCC functions in these malignancies remain inadequately understood. Comprehensive investigations into the interactions among MCC, various signaling pathways, and metabolic processes are essential for uncovering the molecular mechanisms of cancer and the pathological features characteristic of different cancer stages. This review presents the structural characteristics of MCC and its cell growth regulation mechanisms and functional roles within tissues, with the aims of enhancing our understanding of the role of MCC in cancer biology and highlighting potential therapeutic strategies targeting this gene.

Sarcopenia, a disease marked by a progressive loss of muscle mass, increases the risks of disability and metabolic disorders, and decreases quality of life. Current therapeutic options are limited. YY1 transcriptional activity is augmented through an interaction with PHF20 at its promoter region, suppressing muscle differentiation. This study screened sulfasalazine, a medication for managing inflammatory bowel diseases (IBD), using the PHF20-YY1 promoter assay in C2C12 myoblasts from an FDA-approved drug library. Sulfasalazine effectively inhibited PHF20-induced YY1 promoter activity (IC50 = 24 μM), reducing YY1 expression and enhancing muscle-specific gene expression. In mouse models of muscle atrophy, sulfasalazine not only enhanced muscle strength and function but also mitigated muscle loss. Clinical data from patients with IBD revealed that those treated with sulfasalazine had a significantly higher TPI (total psoas index), used as a muscle mass marker, suggesting enhanced muscle preservation. In conclusion, this study suggests the potential for repurposing sulfasalazine to manage sarcopenia, especially associated with IBD.

Over the last decade, the functions of PHD finger protein 20 (PHF20) in several signaling processes have been studied, including those of protein kinase B (PKB)-mediated phosphorylation, p53 regulation, muscle differentiation, and histone modification including histone H3 lysine 4 (H3K4) methylation. One PHF20 human mutation lacks the first nonspecific lethal complex of the component that binds to H3K4me2 to facilitate cancer cell survival. In carcinoma cells, PHF20 expression is regulated by PKB; PHF20 becomes phosphorylated when DNA is damaged, thus inhibiting the p53 activity that maintains cancer cell survival. Given this regulatory effect, PHF20 is usually expressed not only in gliomas but also in breast cancers, colorectal cancers, and other diseases associated with skeletal muscle osteoblastosis and osteoporosis. Thus, PHF20 dysregulation and its downstream effects enhance the abnormalities associated with cancers or other diseases and encourage disease progression. Moreover, PHF20 serves as a nuclear factor kappa-light-chain enhancer of B cell activation, thus increasing pro-inflammatory cytokine production, associated with crosstalk involving the mouse double minute 2 homolog that in turn reduces the normal p53 levels not only in cancers but also in damaged or otherwise injured normal tissues. Despite the findings of various studies, the roles of PHF20 in terms of prognosis, diagnosis, and targeting of disease therapies remain unclear and should be further explored.

Protein kinase B (PKB/AKT) is a very important member of the protein kinase family, playing significant roles in various crucial processes including insulin-signaling, cell survival, growth, and metabolism. The carboxyl-terminal modulator protein 1 (CTMP1) inhibits PKB, primarily by attenuating its phosphorylation. Idiopathic pulmonary fibrosis (IPF) is an irreversible, chronic, progressive pulmonary disorder; the clinical treatment options are limited. Of the various experimental models, bleomycin-induced lung fibrosis is the most extensively studied. It closely resembles human lung fibrosis. We explored the impact of CTMP1 on bleomycin-induced fibrosis. In vitro experiments involved knockdown of CTMP1 in A549 cells (human alveolar epithelial cells), followed by bleomycin treatment. In vivo, lung fibrosis was induced in mice with ablated CTMP1 via intratracheal bleomycin administration at 2 mg/kg. CTMP1 deletion reduced pulmonary fibrosis and the epithelial-to-mesenchymal transition by inhibiting PKB phosphorylation. These findings suggest that CTMP1 plays a pivotal role in the regulation of lung fibrosis, offering new insights into potential therapeutic approaches for IPF patients.

Muscular atrophy, which results in loss of muscle mass and strength, is a significant concern for patients with various diseases. It is crucial to comprehend the molecular mechanisms underlying this condition to devise targeted treatments. MicroRNAs (miRNAs) have emerged as key regulators of gene expression, serving vital roles in numerous cellular processes, including the maintenance of muscle stability. An intricate network of miRNAs finely regulates gene expression, influencing pathways related to muscle protein production, and muscle breakdown and regeneration. Dysregulation of specific miRNAs has been linked to the development of muscular atrophy, affecting important signaling pathways including the protein kinase B/mTOR and ubiquitin‑proteasome systems. The present review summarizes recent work on miRNA patterns associated with muscular atrophy under various physiological and pathological conditions, elucidating its intricate regulatory networks. In conclusion, the present review lays a foundation for the development of novel treatment options for individuals affected by muscular atrophy, and explores other regulatory pathways, such as autophagy and inflammatory signaling, to ensure a comprehensive overview of the multifarious nature of muscular atrophy. The objective of the present review was to elucidate the complex molecular pathways involved in muscular atrophy, and to facilitate the development of innovative and specific therapeutic strategies for the prevention or reversal of muscular atrophy in diverse clinical scenarios.

Shiga toxins (Stxs), produced by Shigella dysenteriae serotype 1 and certain Escherichia coli pathotypes, cause hemorrhagic colitis, which can progress to hemolytic uremic syndrome (HUS) and central nervous system (CNS) pathology. The underlying mechanisms of toxin-induced inflammation remain unclear. The p38 mitogen-activated protein kinase (MAPK) and its downstream target, MAPKAPK2 (MK2), play key roles in various cellular responses. We identified Tristetraprolin (TTP) as a novel substrate of MK2 in Stx-intoxicated cells. Western blot analysis showed that Stxs induce phosphorylation of MK2 (Thr334) and TTP in globotriaosylceramide (Gb3)-positive cells, including DTHP-1 macrophage-like cells and HK-2 renal epithelial cells, but not in Gb3-negative T84 colon carcinoma cells. After treatment with wild-type Stx, the activity of phosphorylated MK2 and TTP persists for up to 8 h, while Stx2amut, which lacks N-glycosidase activity, causes transient MK2/TTP phosphorylation. This suggests that Stxs selectively mediate MK2 and TTP activation in a Gb3- dependent manner. Knockdown of TTP in Stx2a-treated D-THP-1 cells upregulates proinflammatory cytokines such as TNF-alpha, IL-1 beta, IL-6, IL-8, MCP-1, and MIP-1 alpha. The MK2 inhibitor PF-3644022 significantly reduces TTP phosphorylation and blocks the production of IL-6, IL-8, MCP-1, and MIP1 alpha in Stx2a-stimulated HK-2 cells. In conclusion, the MK2-TTP signaling pathway regulates the inflammatory response induced by Stxs in toxin-sensitive cells.

Acyl-coenzyme A thioesterases (ACOTs) are crucial in mediating lipid metabolic functions, including energy expenditure, hepatic gluconeogenesis and neuronal function. The two distinct types are type I and II ACOTs, the latter of which are 'hotdog' fold superfamily members. Type II ACOTs include carboxyl-terminal modulator protein 1 (CTMP1), also termed thioesterase superfamily member 4 (THEM4), and CTMP2, also termed THEM5. Due to their similar structural features and distinct sequence homology, CTMP1 and CTMP2 stand out from other type II ACOTs. CTMP1 was initially known as a protein kinase B (PKB) inhibitor that attenuates PKB phosphorylation. PKB is the central regulator of various cellular functions, including survival, proliferation, growth and metabolism. Therefore, by inhibiting PKB, CTMP1 can affect various cellular processes. Various other functions of CTMP1 have been revealed, including functions in cancer, brain injury, mitochondrial function and lipid metabolism. CTMP2 is a paralog of CTMP1 and was first identified as a cardiolipin remodeling factor involved in the development of fatty liver. As the functions of CTMP1 and CTMP2 were discovered separately, a review to summarize and connect these findings is essential. The current review delineates the intricate complexity of CTMP regulation across different metabolic pathways and encapsulates the principal discoveries concerning CTMP until the present day.

Plant homeodomain finger protein 20 (PHF20) plays a crucial role in various biological processes, but its involvement in renal fibrosis remains unclear. This study investigated the role of PHF20 in renal fibrosis using a unilateral ureteral obstruction (UUO) mouse model, a widely accepted model for chronic kidney disease. PHF20 transgenic (PHF20-TG) and wild-type (WT) mice were utilized to explore how PHF20 influences renal inflammation and fibrosis. After UUO surgery, serum analysis revealed elevated creatinine levels and increased inflammatory markers, indicating worsened renal function in PHF20-TG mice. Histological analyses, including H E, PAS, and Sirius Red staining, confirmed significant tissue damage and fibrosis in the PHF20-TG group. Molecular investigations demonstrated enhanced activation of the TGF-β/SMAD2/3 and NF-κB signaling pathways, both of which are crucial in the progression of renal fibrosis. Our findings suggest that PHF20 overexpression accelerates early-stage renal fibrosis by amplifying inflammatory responses and promoting collagen deposition. This indicates that PHF20 expression could serve as an early marker for renal fibrosis progression.

Muscle atrophy is a debilitating condition with various causes; while aging is one of these causes, reduced engagement in routine muscle-strengthening activities also markedly contributes to muscle loss. Although extensive research has been conducted on microRNAs (miRNAs/miRs) and their associations with muscle atrophy, the roles played by miRNA precursors remain underexplored. The present study detected the upregulation of the miR-206 precursor in cell-free (cf)RNA from the plasma of patients at risk of sarcopenia, and in cfRNAs from the muscles of mice subjected to muscle atrophy. Additionally, a decline in the levels of the miR-6516 precursor was observed in mice with muscle atrophy. The administration of mimic-miR-6516 to mice immobilized due to injury inhibited muscle atrophy by targeting and inhibiting cyclin-dependent kinase inhibitor 1b (Cdkn1b). Based on these results, the miR-206 precursor appears to be a potential biomarker of muscle atrophy, whereas miR-6516 shows promise as a therapeutic target to alleviate muscle deterioration in patients with muscle disuse and atrophy.

IntroductionThe mutated in colorectal cancer (MCC) gene was initially identified as a candidate tumor suppressor gene in colorectal cancer, acting as a negative regulator of cell cycle progression. However, its functional roles in brain tumors, particularly glioblastoma, remain largely unexplored. This study reveals a significant association between MCC status and glioblastoma.MethodsWe explored MCC expression in the glioblastoma database, patient samples, and cell lines. We investigated the proliferation and migration of the cell lines in MCC gene knockdown using small interfering RNA.ResultsIn vitro analyses revealed elevated protein and mRNA levels of MCC in several glioblastoma cell lines (U118MG and T98G). Silencing MCC expression via siRNA-mediated knockdown resulted in increased proliferation and migration of these cell lines. Supporting these findings, analyses of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Genotype-Tissue Expression (GTEx) databases confirmed higher MCC expression in glioblastoma tumors than in normal brain tissue. Importantly, we observed that high MCC expression was associated with poor prognosis in glioblastoma patients, highlighting its potential role in disease progression. Additionally, this study identifies a nuclear localization of MCC in the glioblastoma cell line.DiscussionThese findings indicate that MCC expression is significantly upregulated in glioblastoma and may play a role in its pathophysiology, warranting further investigation.

Supplementary Figure 2 from Association of LETM1 and MRPL36 Contributes to the Regulation of Mitochondrial ATP Production and Necrotic Cell Death

Mitochondrial methionyl-tRNA synthetase (MARS2) canonically mediates the formation of fMet-tRNAifMet for mitochondrial translation initiation. Mitochondrial calcium uniporter (MCU) is a major gate of Ca2+ flux from cytosol into the mitochondrial matrix. We found that MARS2 interacts with MCU and stimulates mitochondrial Ca2+ influx. Methionine binding to MARS2 would act as a molecular switch that regulates MARS2-MCU interaction. Endogenous knockdown of MARS2 attenuates mitochondrial Ca2+ influx and induces p53 upregulation through the Ca2+-dependent CaMKII/CREB signaling. Subsequently, metabolic rewiring from glycolysis into pentose phosphate pathway is triggered and cellular reactive oxygen species level decreases. This metabolic switch induces inhibition of epithelial-mesenchymal transition (EMT) via cellular redox regulation. Expression of MARS2 is regulated by ZEB1 transcription factor in response to Wnt signaling. Our results suggest the mechanisms of mitochondrial Ca2+ uptake and metabolic control of cancer that are exerted by the key factors of the mitochondrial translational machinery and Ca2+ homeostasis.

Supplementary Figure Legends 1-7, Methods from Association of LETM1 and MRPL36 Contributes to the Regulation of Mitochondrial ATP Production and Necrotic Cell Death