This study investigates the role of Gasdermin D (GSDMD)-mediated pyroptosis in the pathogenesis of necrotizing enterocolitis (NEC) and reveals the mechanism by which reactive oxygen species (ROS) promote intestinal inflammation and injury through NLRP3/GSDMD pathway activation. Analysis of human NEC tissue samples showed significant oxidative stress (elevated MDA, decreased SOD activity, reduced GSH/GSSG ratio) and activation of the NLRP3/GSDMD/IL-1β pathway in the intestines of NEC patients. In an experimental NEC mouse model, GSDMD knockout (GSDMD-/-) significantly delayed NEC onset, reduced incidence, attenuated intestinal damage, and improved survival. GSDMD deficiency also decreased macrophage pyroptosis, systemic inflammation, and bacterial translocation, while improving intestinal barrier function. Pharmacological inhibition of GSDMD (using disulfiram) similarly mitigated pyroptosis and enhanced the bactericidal capacity of macrophages. Further mechanistic studies indicated that ROS drive pyroptosis by activating GSDMD, and the antioxidant N-acetyl-l-cysteine (NAC) could reverse this effect. The findings suggest that GSDMD is a potential therapeutic target for NEC, and strategies targeting GSDMD inhibition (genetic or pharmacological), combined with antioxidant therapy, may offer novel treatment approaches for NEC.
Dictyostelium discoideum is a cellular model that has been widely used in cell signal research focusing on different cellular and developmental processes. The unique lifecycle of these cells-which involves switching between vegetative and development phases-makes Dictyostelium a reliable model for investigations in this field. The ability to switch between these phases depends mainly on the availability of nutrients. Specifically, the vegetative phase of Dictyostelium cells is initiated when food is plentiful. This phase is characterized by the unicellular form of this organism, in which it is able to hunt for bacteria and actively divide by mitosis. However, when nutrients are depleted, certain cellular signals are activated that stimulate the development phase, which commences with cell chemotaxis toward cyclic AMP to form aggregates. Based on previously collected data, aggregation-regulating signals in Dictyostelium are thoroughly explained herein. Heterotrimeric G protein signals and downstream effectors are thought to be included in this paradigm, as blocking these signals leads to the aggregation-minus phenotype. Recently, Dictyostelium was used to detect the effect of natural products, some of which caused a noticeable delay of the aggregation stage. However, no clear evidence has been obtained that explains why aggregation is delayed or the science behind this phenomenon. This review provides insights into regulatory factors, beyond the key aggregation regulators, that possibly contribute to the aggregation-delayed phenotype of Dictyostelium cells. The discussion in this review will enhance understanding of the importance of divalent cations/ions in this phenotype.
Sodium-glucose cotransporter (SGLT) inhibitors are increasingly recognised for anticancer activity beyond their established glycaemic effects. While selective SGLT2 inhibitors have been reported to suppress tumour cell proliferation and modulate AMPK/mTOR and PI3K/AKT signalling, whether dual SGLT1/2 inhibition is associated with modulation of epigenetic regulators has remained largely unexplored. Here, we investigated the anticancer effects of sotagliflozin, a dual SGLT1/2 inhibitor, in breast (MCF-7) and lung (A549) cancer cells. Sotagliflozin reduced cell viability, clonogenic survival, migration, and invasion, and these effects were accompanied by G2/M cell-cycle arrest, increased AMPK activation, and changes in PTEN-AKT-mTOR signalling. Molecular docking analysis predicted favourable interactions between sotagliflozin and DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), with the strongest predicted binding to DNMT1 (-8.9 kcal/mol). Consistent with these computational predictions, sotagliflozin treatment was associated with reduced total DNMT enzymatic activity, decreased DNMT1 mRNA and protein abundance, and reduced protein abundance of class I and class II histone deacetylases (HDAC1-4 and HDAC6) in both cell lines. In addition, sotagliflozin treatment was associated with autophagy-related changes, including increased acidic vesicular organelles together with elevated LC3-II and Beclin-1 protein abundance. Collectively, these findings demonstrate that sotagliflozin exerts broad anticancer effects in breast and lung cancer cells and provide preliminary evidence that its treatment is associated with modulation of DNMT1 and HDAC expression. Further studies are required to determine whether these epigenetic changes contribute directly to the observed cellular responses or represent downstream consequences of metabolic perturbation.
The development of tuberculosis (TB) is dictated by a complicated interplay between antimicrobial defense and host-mediated immunopathology. Neutrophils are known to exhibit striking functional plasticity with phenotypes associated with both bacterial containment and tissue damage. However, the mechanisms that connect the granuloma microenvironment to neutrophil fate remain poorly understood. This review aims to fill this gap by integrating emerging evidence that defines immunometabolic adaptation as a key determinant of neutrophil plasticity in TB. The core of this analysis delineates how the spatially organized granuloma characterized by hypoxia, nutrient limitation, iron dysregulation, and extracellular acidosis imposes metabolic pressures that remodel neutrophil function. Environmental signals converge on regulatory networks, including HIF-1α, mTOR/AMPK signaling, glycolytic pathways, the pentose phosphate pathway, and redox control systems, thereby affecting the switch between antimicrobial activity and pathological inflammation. This paradigm presents metabolic rewiring as a potentially important determinant of neutrophil fate in TB and offers a mechanistic view of how protective antimicrobial programs could evolve into dysfunctional states characterized by excessive NETosis, matrix destruction, ferroptotic stress, and tissue injury. Ultimately, a better understanding of these metabolic checkpoints may provide opportunities for the development of host-directed therapeutic approaches to enhance protective neutrophil functions while limiting immunopathology.
Wang et al. recently proposed mitoxyperiosis as a previously uncharacterized, mitochondria-dependent form of lytic cell death triggered by immunometabolic stress. Unlike apoptosis, pyroptosis, necroptosis, or ferroptosis, mitoxyperiosis is driven by sustained oxidative stress and prolonged mitochondria-plasma membrane contact, culminating in localized oxidative membrane damage and non-caspase-dependent rupture, termed mitoxyperilysis. Central to this mechanism is the activation of mechanistic target of rapamycin complex 2 (mTORC2), which suppresses actin cytoskeletal remodeling and inhibits lamellipodia formation, thereby retaining mitochondria at the cell periphery. Remarkably, mTORC2 inhibition or the restoration of cytoskeletal dynamics prevents membrane rupture despite persistent oxidative stress. This review synthesizes mechanistic insights and experimental evidence underlying mitoxyperiosis and examines its implications for tumor biology and inflammatory disease. We further discuss how this pathway may expand current understanding of spatial control in regulated cell death and may provide therapeutic opportunities targeting mitochondrial positioning and mTORC2 signaling in immunometabolic disorders.
Our group has previously described the infection course of Leishmania amazonensis in BALB/c and BALB/cnu/nu mice, which have distinct T-cell dependent responses. In this study, lesion-derived amastigotes exhibited differential protein expression in a host-dependent manner. Herein, we evaluate the impact of the immune system of these two mouse strains on parasite survival and virulence. For this, BALB/c and BALB/cnu/nu mice were infected with promastigotes of the LV79 strain, and after 13-weeks of infection, amastigotes were isolated from the lesion footpads. The amastigotes recovered from BALB/c mice were more viable, generating cultures with a higher number of promastigotes than those from BALB/c nude mice. Accordingly, lesion-derived amastigotes from BALB/c mice displayed higher infectivity, induced larger parasitophorous vacuoles in vitro, and exhibited greater virulence in vivo than those from BALB/cnu/nu mice. These findings demonstrate that the mouse immune environment can shape the biological phenotype of the parasite, directly impacting its survival and virulence.
Chronic atrophic gastritis (CAG) with intestinal metaplasia (IM) is a key precancerous lesion that may progress to intestinal-type gastric adenocarcinoma. Piwei Peiyuan Pill (PPP) has shown significant clinical efficacy in ameliorating CAG with IM, but its active components and underlying mechanisms remain unclear. High-performance liquid chromatography (HPLC) and ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) were used to identify the components of PPP and the active ingredients in PPP-containing serum. The therapeutic efficacy and potential mechanisms of PPP were further investigated via transcriptomic sequencing and experimental validation. UHPLC-HRMS analysis of PPP-containing serum identified several bioactive components, including esculin, lithospermic acid, and atractylenolide III. In CAG rats, PPP significantly ameliorated gastric mucosal damage and reduced serum IL-6 and TNF-α levels. Transcriptomic results showed that IRAK1 was highly expressed in CAG patients with IM and associated with activation of the NF-κB pathway. PPP intervention dose-dependently suppressed hyperactivation of the Pellino1/IRAK1/NF-κB axis and decreased the expression of intestinal metaplasia markers CDX1 and MUC2. Additionally, PPP improved immune function by increasing the proportion of CD4+ T cells and decreasing the proportion of CD8+ T cells in CAG model rats. Taken together, these findings suggest that PPP mitigates CAG and attenuates IM at least in part by suppressing the Pellino1/IRAK1/NF-κB signaling pathway, indicating that it may serve as a promising therapeutic strategy for reducing inflammation-associated gastric carcinogenesis.
Berberine (BBR), a natural alkaloid, exhibits potent anti-tumor activity in colorectal cancer (CRC), but its mechanisms are not fully elucidated. Analysis of GEO datasets (GSE216908 and GSE184414) identified WDR54 as a key target of BBR treatment. In vitro, BBR treatment of CRC cell lines (HT-29 and SW480) markedly inhibited cell proliferation, DNA synthesis, and colony formation. Notably, BBR triggered G1-phase cell cycle arrest and promoted apoptosis, as validated by flow cytometry and molecular marker analysis. WDR54 overexpression partially rescued these anti-tumor effects, confirming its functional importance. Mechanistically, cellular thermal shift assays (CETSA) and mRNA stability assays revealed that BBR suppresses WDR54 expression via indirect transcriptional inhibition rather than direct protein binding or altered mRNA stability. Dual-luciferase reporter assays further confirmed that BBR dose-dependently inhibits WDR54 promoter activity. In vivo, an AOM/DSS-induced CRC mouse model showed that BBR reduced tumor number and size, alleviated pathological progression, and suppressed the WDR54/β-catenin axis. These findings suggest that BBR exerts significant anti-tumor effects in CRC by downregulating WDR54 and inhibiting Wnt/β-catenin signaling, highlighting WDR54 as a potential therapeutic target and BBR as a promising treatment for CRC.
Diabetic nephropathy (DN) is a one of the common microvascular complication of diabetes that involves oxidative stress, inflammation, activation and overexpression of Nuclear factor kappa B (NF-κB), and chronic renal dysfunction. In this study, we evaluated the renoprotective role of perillaldehyde (PA) in protecting kidneys from diabetic nephropathy using in vitro and in vivo models of Streptozotocin-induced diabetic nephropathy. PA pre-treatment of NRK-52E cells under high-glucose conditions resulted in a significant reduction of reactive oxygen species formation, up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), suppression of Kelch-like ECH-associated protein 1 (Keap1), and elevation of antioxidant enzyme biomarkers, such as heme oxygenase 1, superoxide dismutase 1, and NAD(P)H dehydrogenase quinone 1. PA also inhibited the overexpression of NF-κB, inducible nitric oxide synthase, and poly (ADP-ribose) polymerase in high-glucose exposed NRK-52E cells. Administration of PA (35 and 70 mg/kg) to streptozotocin-induced diabetic rats showed beneficial effects on renal function parameters such as creatinine and blood urea nitrogen. PA treatment attenuated glomerular and tubular structural damage, as evidenced by H&E and PAS staining. At molecular level, PA was found to maintain the redox balance in the kidneys by stimulating the Nrf2/Keap1/HO-1 signalling pathway and inhibiting the NF-κB-dependent inflammatory response. Moreover, PA lowered lipid peroxidation and enhanced antioxidant status via reduction in MDA and elevation in GSH. The above results indicated that PA showed considerable reno-protective actions through coordinated regulation of both oxidative stress and inflammation pathways in experimental models of diabetic nephropathy.
This study explores the mechanism of TRIM16 on osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in an inflammatory microenvironment. hPDLSCs were cultured and identified by flow cytometry and osteogenesis/adipogenesis induction. hPDLSCs were maintained with P. gingivalis LPS and induced by osteogenic differentiation. TRIM16, HOXA10, and KLF5 expression was tested via RT-qPCR and Western blot. After overexpression of TRIM16, TNF-α, IL-6, and IL-1β levels were examined via ELISA. Osteogenic differentiation of hPDLSCs was validated by Alizarin red staining, ALP staining, and Western blot. The binding of TRIM16 to HOXA10 was detected by Co-IP, and the ubiquitinated HOXA10-containing complexes were measured. Dual luciferase assay and ChIP analyzed the enrichment of HOXA10 on the KLF5 promoter. LPS treatment reduces TRIM16 and KLF5 expression, while elevating HOXA10 protein level. Overexpression of TRIM16 alleviates inflammation in LPS-induced hPDLSCs and enhances osteogenic differentiation. Mechanistically, TRIM16 inhibits HOXA10 protein level via ubiquitination, thereby abating the enrichment of HOXA10 on the KLF5 promoter and promoting the expression of KLF5. In conclusion, TRIM16 facilitates osteogenic differentiation of hPDLSCs in an inflammatory microenvironment via HOXA10/KLF5 axis.
Adipose tissue plays a critical role in determining the characteristic palatability of Japanese Black cattle beef, including its distinctive aroma, tenderness, and flavor. These quality traits are closely associated with adipogenic differentiation and lipid metabolism; however, the underlying molecular mechanisms remain poorly understood. Adipose-derived stromal cells (ASCs) residing within adipose tissue possess the capacity to differentiate into adipocytes and other mesenchymal lineages and are, therefore, considered valuable experimental resources for adipose tissue research. Nevertheless, primary cells are subject to several limitations, including a restricted proliferative lifespan caused by culture-induced stress and reduced experimental reproducibility due to inter-individual variability, which hamper their use in long-term in vitro analyses. In this study, we immortalized ASCs derived from Japanese Black cattle using the K4DT method, which involves the introduction of the R24C mutant form of cyclin-dependent kinase 4 (CDK4R24C), Cyclin D1, and telomerase reverse transcriptase. The established bovine ASCs (bASCs) [bASCs-K4DT] exhibited a stable proliferative capacity during long-term culture while retaining their ability to undergo adipogenic differentiation. These immortalized bASCs may serve as a useful in vitro model for elucidating the molecular mechanisms underlying adipocyte differentiation and formation of breed-specific aroma and flavor characteristics.
Cytokeratins are widely used as epithelial markers in diagnostic pathology and flow cytometry, and malignant lymphomas are generally considered cytokeratin-negative except for undifferentiated large cell lymphomas. During antibody screening experiments using flow cytometry, intracellular cytokeratin signals were unexpectedly detected in cultured lymphoma cell lines after cell permeabilization. Although cytokeratin is a component of the cytoskeleton, this finding raised concerns regarding the interpretation of cytokeratin positivity in lymphoid cells. To elucidate the nature of cytokeratin detection in lymphomas, cultured T-cell, B-cell, and natural killer cell lymphoma lines were analyzed using immunohistochemistry, flow cytometry, and quantitative RT-PCR (qRT-PCR), with epithelial carcinoma cell lines and keratin-free cells as references. Because malignant lymphomas disseminate systemically, we examined whether this behavior was associated with epithelial-mesenchymal transition-like features. Cytokeratins were not detected on the cell surface of lymphoid or epithelial cells but were detected intracellularly in multiple lymphoma cell lines. qRT-PCR confirmed the expression of multiple keratin transcripts in lymphoid cells, without correlation with epithelial-mesenchymal transition-related markers, including CDH1. These findings indicate that intracellular cytokeratin detection can occur in lymphoma cell lines without evidence of epithelial differentiation or association with EMT-related markers and should be considered when interpreting cytokeratin positivity.
Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact sites between the endoplasmic reticulum (ER) and mitochondria that coordinate multiple cellular processes such as calcium signaling, lipid trafficking, and redox homeostasis. Increasing evidence shows that cancer cells remodel MAMs to support metabolic adaptation, stress tolerance, tumor progression, and therapeutic resistance. In this review, we summarize the structural organization of MAMs, the core tethering and regulatory mechanisms governing their plasticity, and emerging evidence linking MAM dysfunction to malignant phenotypes and therapeutic resistance. We highlight that the roles of MAM-associated proteins in cancer are highly context-dependent, varying with tumor type, metabolic state, and therapeutic pressure. We further discuss emerging therapeutic strategies targeting MAM-associated pathways, as well as combination approaches to overcome resistance. A better mechanistic understanding of MAM remodeling may reveal actionable vulnerabilities and support biomarker-guided precision therapy across cancer types.
Lymph node metastasis is a pivotal determinant of poor prognosis of gastric cancer, but the molecular orchestrators of lymphatic dissemination remain poorly characterized. Recent research highlights the pivotal role of small extracellular vesicles (sEVs) with specific cargo during the process. Herein, TLN1 was identified as being selectively enriched within sEVs from highly lymph-metastatic gastric cancer cells and in the serum of gastric cancer patients with lymph node metastasis, as identified through proteomic screening and confirmed by western blotting. sEVs act as key autocrine signals that influence gastric cancer cell behaviors such as proliferation, migration, invasion, and adhesion. TLN1 protein levels in cells correlate with their lymphatic metastatic potential and determine TLN1 content in sEVs. Inhibiting TLN1 reduces these cancer cell malignant behaviors and leads to TLN1-depleted sEVs. TLN1 could be transferred to gastric cancer cells and human lymphatic endothelial cells (HLECs) via sEVs. Without TLN1, sEVs cannot enhance cancer cell malignancy or induce HLEC proliferation, tube formation, adhesion, permeability in vitro, or lymphatic metastasis in vivo. Mechanistically, AKT activation was identified as a mediator of the effects exerted by sEV-TLN1 on both gastric cancer cells and HLECs. In conclusion, TLN1 orchestrates lymphatic metastasis in gastric cancer by dual-modulating tumor cell malignancy and lymphatic vessel remodeling via AKT activation. This discovery offers new perspectives on the mechanisms driving lymphatic metastasis in gastric cancer and proposes a promising target for the detection and therapeutic intervention of lymph node metastasis.
Diabetes mellitus is a chronic metabolic disorder characterized by the loss or dysfunction of insulin-producing beta (β) cells. Adipose-derived stem cells (ADSCs) represent a promising source for generating functional insulin-producing β cells due to their accessibility and differentiation potential. Photobiomodulation (PBM), a non-invasive light-based therapy, has emerged as an innovative strategy to enhance stem cell differentiation efficiency. Evidence suggests that green (525 nm) and near-infrared (825 nm) wavelengths, applied individually or in combination, can modulate cellular metabolism, ATP production, and differentiation-related signaling pathways, thereby influencing ADSC commitment toward insulin-producing β-cell-like phenotypes. This in vitro study evaluated the effects of PBM at 525 nm and 825 nm, delivered individually and in combination at energy fluences of 5 J/cm2 and 10 J/cm2, on the differentiation of ADSCs cultured in β-cell induction medium into insulin-producing β-cell-like cells under two-dimensional (2D) culture conditions at 24 h, 5 days, and 10 days. Cellular responses were evaluated using adenosine triphosphate (ATP) luminescence assays, lactate dehydrogenase (LDH) activity assays, Giemsa staining, Live/Dead viability assays, and dithizone (DTZ) staining. ATP levels varied significantly among the experimental groups, reflecting changes in cellular metabolic activity associated with β-cell induction and PBM exposure, and reduced LDH activity, suggesting decreased cytotoxicity. Giemsa staining revealed morphological changes consistent with β-cell differentiation, while Live/Dead assays demonstrated the maintenance of cell viability across all experimental groups. Dithizone staining identified the presence of zinc-rich insulin-producing clusters. These findings highlight the importance of PBM wavelength and fluence optimization in regenerative stem cell applications.
Mechanobiology has emerged as a critical regulator of cellular metabolism, linking physical forces to transcriptional, metabolic, and epigenetic adaptations across multiple organ systems. However, the mechanisms by which extracellular matrix (ECM) dynamics and mechanotransduction pathways coordinate metabolic reprogramming in physiological and pathological conditions remain incompletely understood. This review provides a focused mechanometabolic framework integrating cardiovascular, skeletal, and endocrine systems through the convergence of ECM remodeling, cytoskeletal tension, and force-dependent signaling pathways. Central to this framework is the YAP/TAZ signaling axis, which functions as a mechanosensitive transcriptional regulator downstream of integrin-focal adhesion kinase (FAK)-Src, RhoA/ROCK, actomyosin tension, and Hippo-dependent and Hippo-independent signaling networks. These pathways regulate metabolic programs involving glycolysis, mitochondrial function, redox homeostasis, and anabolic biosynthesis through downstream targets including GLUT1, HK2, PFKFB3, and mitochondrial regulatory pathways. The review critically examines how aberrant mechanotransduction contributes to cardiovascular remodeling, endothelial dysfunction, fibrosis, and metabolic disease progression, while also discussing the context-dependent roles of YAP/TAZ signaling in adaptive versus pathological responses. In skeletal metabolism, the gut-bone axis is presented as a bidirectional mechanochemical network in which microbiota-derived metabolites, osteoimmune signaling, and biomechanical loading coordinately regulate bone remodeling and systemic metabolism. Furthermore, the review evaluates emerging evidence linking viscoelasticity, mitochondrial dynamics, and immunometabolism to disease progression and therapeutic responsiveness. Advances in mechanobiomaterials and regenerative strategies are also discussed, emphasizing their ability to modulate cellular energetics and mechanotransduction pathways to restore tissue homeostasis. Finally, current limitations in mechanobiology research, including model heterogeneity, tissue-specific mechanical responses, and translational barriers, are highlighted. Collectively, this review establishes mechanobiology as a systems-level regulator of metabolic reprogramming and underscores the therapeutic potential of targeting mechanometabolic pathways in human disease.
The Epidermal Growth Factor Receptor (EGFR) is a key regulator of neurodevelopment, controlling the proliferation, differentiation, and self-renewal of neural stem and progenitor cells. Dysregulated EGFR signaling has been implicated in schizophrenia, a neurodevelopmental disorder associated with abnormal cortical maturation. We investigated EGFR-dependent signaling in neural stem/progenitor cells derived from olfactory neuroepithelium (hereafter referred to as Olfactory Neural Stem/Progenitor Cells, ONSPCs) collected from individuals with no prior history of psychiatric disorders (hereafter referred to as healthy controls, HC) and patients diagnosed with schizophrenia (schizophrenic, SZ), an ex vivo human model that retains disease-related molecular signatures. Both HC- and SZ-derived ONSPCs formed neurospheres under proliferative conditions in the presence of the growth factors Epidermal Growth Factor (EGF) and Fibroblast Growth Factor (FGF), confirming their neural progenitor identity. However, under EGF-exclusive conditions, HC-derived ONSPCs generated compact, well-organized neurospheres, whereas SZ-derived ONSPCs produced sparse, irregular aggregates, indicating impaired responsiveness to EGF. Despite comparable EGFR protein levels between groups, EGF stimulation revealed distinct dynamics of downstream EGFR effectors. In HC-derived ONSPCs, EGFR activation was initially modest but sustained over time, whereas in SZ-derived cells it was more rapid and transiently stronger, followed by early signal decay. In particular, Akt and Src, which are implicated in signaling pathways driving proliferation and self-renewal, displayed activation dynamics paralleling those of EGFR in each group. These findings are consistent with dysregulation of the magnitude and temporal dynamics of EGFR-dependent signaling in SZ-derived ONSPCs, associated with impaired neurosphere formation under EGF-exclusive conditions and suggestive of reduced self-renewal capacity. Although limited by the modest sample size, the semiquantitative nature of Western blot analyses, and the potential effect of medication exposure, this study supports the relevance of patient-derived ONSPCs as a physiologically meaningful platform for investigating neurodevelopmental mechanisms underlying schizophrenia.
Glioblastoma (GBM) is a highly aggressive intracranial malignancy originating from neuroepithelial glial progenitors. The prominent intra- and intertumoral heterogeneity of GBM is a major driver of therapeutic resistance and frequent tumor recurrence. Cholesterol is an essential structural component of mammalian cell membranes and plays crucial roles in membrane trafficking and transmembrane signal transduction. As a key intracellular cholesterol transporter, the Niemann-Pick type C2 (NPC2) protein remains poorly characterized regarding its biological functions and clinical implications in GBM. In this study, immunohistochemical staining of clinical GBM specimens revealed that elevated NPC2 expression was significantly correlated with unfavorable patient prognosis. Consistent with clinical observations, genetic knockdown of NPC2 markedly suppressed the proliferation and invasion abilities of LN18 cells. Mechanistically, NPC2 silencing downregulated GPX4 expression at both transcriptional and translational levels, suggesting a potential regulatory relationship between NPC2 and the ferroptosis pathway. Collectively, these findings indicate that NPC2 may facilitate GBM malignant progression partially through modulating GPX4-mediated ferroptosis, thereby representing a tentative prognostic biomarker and a potential therapeutic target for GBM that requires further validation.
Gastric cancer remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for novel biomarkers and therapeutic targets. Ribosomal proteins have recently emerged as critical regulators of tumorigenesis beyond their classical roles in protein synthesis. Here, we investigated the expression, functional significance, and underlying mechanism of RPL27 in gastric cancer. RPL27 was markedly upregulated in gastric cancer tissues compared with adjacent normal tissues, as demonstrated by Western blotting and immunohistochemistry. High RPL27 expression was significantly associated with poor overall survival, suggesting its potential as a prognostic biomarker. Functional assays revealed that RPL27 knockdown substantially suppressed gastric cancer cell proliferation, migration, and invasion. Transcriptomic analysis identified FMC1 as a key downstream molecule of RPL27, mediating its regulatory effects on mitochondrial function, including alterations in membrane potential, morphology, DNA copy number, and ATP5A expression. Rescue experiments demonstrated that either FMC1 knockdown or treatment with the OXPHOS inhibitor oligomycin A partially reversed the malignant phenotypes induced by RPL27 overexpression. Furthermore, RPL27 knockdown significantly inhibited tumor growth in a xenograft mouse model. Collectively, these findings establish RPL27 as a novel oncogenic driver in gastric cancer and demonstrate that it promotes tumor progression through FMC1-dependent regulation of oxidative phosphorylation. The RPL27-FMC1-mitochondrial function axis may thus represent a promising vulnerability for therapeutic intervention in gastric cancer.
