SEARCH · Search PubMed

Results for “Regulated cell death”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

569 recordsLinked to original sources

PubMed2026

A Multi-omics Regulated Cell Death Framework Defines Immune Phenotypes and Guides Precision Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is molecularly and immunologically heterogeneous, contributing to variable treatment response. Because regulated cell death (RCD) intersects with tumor metabolism, immune regulation, and therapeutic susceptibility, we built an RCD-centered framework for CRC stratification. Multi-cohort transcriptomic data were used to infer RCD subtypes with non-negative matrix factorization (NMF) and non-negative least squares (NNLS). Genomic, bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomic datasets were integrated to characterize subtype-associated biology. Machine-learning models were developed for immunotherapy response and survival-risk estimation. Candidate compounds were screened by GDSC2-based drug-sensitivity modeling and molecular docking, and FSTL3 was functionally assessed in vitro. The framework separated CRC samples into two RCD-related phenotypes resembling immune-hot and immune-cold states. RCD1 showed immune activation and higher mutational burden, whereas RCD2 showed immune-suppressed features, intratumoral heterogeneity, and aggressive biology. RCD-associated signatures showed potential for predicting immunotherapy response and survival risk. Dasatinib was prioritized for immune-cold, high-risk tumors, with preliminary evidence supporting its activity in CRC cells, while functional assays suggested a role for FSTL3 in growth, invasion, epithelial-mesenchymal transition, and apoptosis regulation. These findings suggest that RCD-based multi-omics analysis may refine CRC stratification and help generate therapeutic hypotheses.

Colorectal cancer↗

PubMed2026

Targeting Gasdermins for Therapeutic Interventions in Central Nervous System Injury.

Central nervous system (CNS) injuries are the leading cause of permanent disability and premature death in adults worldwide, with their incidence continuing to rise amid social development. These injuries not only severely impair the quality of life but also impose a heavy burden on the global public health system. Current clinical interventions, such as decompression and thrombolysis, can alleviate primary injury but fail to effectively reverse the secondary neuroinflammatory damage. Traditional anti-inflammatory therapies, which cannot block the upstream source of the inflammatory cascade, have led to repeated failures in global clinical translation research over the past decades. Gasdermins were first characterized in studies of systemic inflammatory diseases. These proteins form transmembrane pores to drive the release of proinflammatory factors and inflammatory cell death, serving as key mediators of host innate immunity. Recent studies have revealed that gasdermins play critical roles in regulating the initiation and amplification of neuroinflammation following CNS injury. To clarify the therapeutic potential of gasdermins as targets for injury repair, this review systematically summarizes the structure and function of gasdermins, as well as their cell-specific activation and regulatory mechanisms. We further elaborate on their pathological roles in these injuries and the corresponding therapeutic strategies, aiming to provide a theoretical reference for basic research and clinical translation in this field.

Humans↗

PubMed2026

Lipid-mediated activation of BLT2 promotes membrane repair to prevent cell death.

Various pathogenic microorganisms produce toxins that create pores in cell membranes, causing cell damage and disrupting the host epithelial barrier. Recently, we reported that mice lacking the G protein-coupled receptor leukotriene B4 receptor 2 (BLT2), which is expressed in vascular endothelial and alveolar epithelial cells, are highly susceptible to pneumolysin (PLY), a pneumococci-generated toxin. Although we clarified the protective roles of BLT2 in vascular endothelial cells, those in alveolar epithelial cells have not been elucidated. Here, we report that lipid mediator 12-hydroxyheptadecatrienoic acid (12-HHT), which is produced by membrane-damaged epithelial cells, prevents cell death by promoting membrane repair through BLT2. BLT2 promoted the release of PLY-bound plasma membranes as extracellular vesicles in a sphingomyelinase-dependent manner. Additionally, BLT2 activated Rac1 and subsequent actin polymerization, leading to resistance to cell death. Furthermore, inhibition of 12-HHT production by aspirin and treatment with a BLT2 antagonist abolished the protective effect of BLT2. These findings provide a new therapeutic strategy for bacterial infection.

Receptors, Leukotriene B4↗

PubMed2026

Transcriptomic insights into the coordinated regulation of signaling, apoptosis, immunity, and metabolism during Sinonovacula constricta larval metamorphosis.

Metamorphosis is a critical ontogenetic transition for marine bivalves, marking the shift from planktonic to benthic lifestyles, where successful transformation dictates survival. The razor clam Sinonovacula constricta is economically important; however, low larval metamorphosis rates remain a major bottleneck in seedling production. To elucidate the mechanisms governing this process, we performed a comparative transcriptome analysis of S. constricta larvae at pre- and post-metamorphosis stages using Illumina sequencing. A total of 3701 differentially expressed genes (DEGs) were identified, including 3254 up-regulated and 447 down-regulated genes. Functional annotation of the respective top 20 significantly up-regulated and down-regulated DEGs indicated their potential pivotal roles in signal transduction (e.g., up-regulated: CAV1, CHRNA2; down-regulated: APP, NOTCH1), cellular proliferation and differentiation (e.g., up-regulated: TUBA, EGF1; down-regulated: KIF23, TTC25), transcriptional and epigenetic regulation (e.g., up-regulated: NFIL3; down-regulated: OVO, HMX1), substance transport (e.g., up-regulated: LRP2, LRP1B; down-regulated: SLC51A, Slc33a1), substance metabolism (e.g., up-regulated: CPK3, CYP26A1; down-regulated: RDMT1, ADAC), immunomodulation (e.g., up-regulated: CPN2, CRISP2), and protein homeostasis (e.g., up-regulated: HSP27, NAS-27). Functional enrichment analysis further revealed that DEGs were significantly enriched in pathways related to signal transduction and developmental regulation (e.g., Ras, TNF), cell death and homeostasis (e.g., apoptosis), immune responses (e.g., Toll-like receptor), energy metabolism (e.g., lipid), cardiovascular related (e.g., Fluid shear stress), cell junction and architecture (e.g., Tight junction), and infectious disease (e.g., measles). These results suggest a synergistic interplay between signaling, apoptosis, immunity, and metabolism during S. constricta metamorphosis. This study advances our understanding of marine bivalve metamorphosis and offers candidate genes for further mechanistic studies.

Animals↗

PubMed2025

The molecular mechanism of cuproptosis and research progress in pancreatic diseases.

PURPOSE: Cuproptosis has been proven to be a novel mode of cell death, distinct from other types of cell death such as necrosis, ferroptosis, pyroptosis, and apoptosis. This study aims to systematically review the molecular mechanisms of cuproptosis in recent years and its research progress in pancreatic diseases. METHODS: By searching PubMed and Web of Science databases, 113 key literatures were included for thematic analysis, covering the molecular mechanism of cuproptosis and its role in the occurrence and development of pancreatic cancer, acute and chronic pancreatitis, diabetes, pancreatic cyst, pancreatic injury and pancreatic neuroendocrine tumor. RESULTS: Cuproptosis refers to the accumulation of copper ions in cells, which leads to instability of ferritin and aggregation of acylated proteins, resulting in oxidative stress-related cell death. Recent studies have shown that cuproptosis plays an important role in the occurrence and development of various pancreatic diseases, such as pancreatic cancer, acute and chronic pancreatitis, diabetes, pancreatic cysts, pancreatic injuries and pancreatic neuroendocrine tumor. The inducers of cuproptosis, such as disulfiram, chloroquinolones, and perilla phenols, alleviate pancreatic cancer by promoting cell cuproptosis. Copper chelators such as tetraethylenepentamine and tetrathiomolybdate promote the recovery of pancreatic injury by inhibiting cell cuproptosis. CONCLUSIONS: Cuproptosis plays a crucial role in the pathogenesis of pancreatic diseases. Further research on the cuproptosis pathway may become a potential target for the treatment of pancreatic diseases.

Animals↗

PubMed2026

Pembrolizumab-Chemotherapy Versus Pembrolizumab in Head and Neck Squamous Cell Carcinoma: A PD-L1 CPS-Stratified Analysis of Updated KEYNOTE-048 Data.

Based on KEYNOTE-048, pembrolizumab monotherapy and pembrolizumab-chemotherapy are established category 1 first-line treatments for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1. We compared their efficacy using updated trial data. We analyzed 4-year progression-free survival on next-line therapy (PFS2) and 5-year overall survival (OS) data from KEYNOTE-048 by reconstructing time-to-event data using KMSubtraction. Efficacy was compared in CPS 1-19 and CPS ≥ 20 subgroups using Kaplan-Meier estimates, Cox models, restricted mean survival time (RMST), and landmark analyses. Among 499 patients with CPS ≥ 1, 240 (48.1%) had CPS 1-19 and 259 (51.9%) had CPS ≥ 20. In the CPS 1-19 subgroup, pembrolizumab-chemotherapy showed numerically longer median PFS2 (10.1 vs. 8.0 months; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.62-1.06) and OS (12.8 vs. 10.8 months; HR: 0.87; 95% CI: 0.67-1.15) versus monotherapy, without statistical significance. For CPS ≥ 20 patients, efficacy was comparable between regimens, with similar median PFS2 (11.3 vs. 11.7 months; HR: 0.95) and OS (14.7 vs. 14.9 months; HR: 0.96). RMST and landmark analyses showed an early PFS2 benefit and a trend toward OS benefit with pembrolizumab-chemotherapy in CPS 1-19, with comparable outcomes in CPS ≥ 20. Pembrolizumab-chemotherapy showed a trend toward improved outcomes in the CPS 1-19 subgroup, with comparable efficacy in the CPS ≥ 20 subgroup, supporting a refined first-line strategy: monotherapy for CPS ≥ 20 to minimize toxicity, and combination therapy for CPS 1-19 to potentially enhance disease control.

Humans↗

PubMed2026

Design, rationale, and baseline patient characteristics for the Sickle Cell Disease and CardiovAscular Risk-Red cell Exchange (SCD-CARRE) trial.

BACKGROUND: Despite wide utilization of automated red blood cell exchange (RBCX) transfusion in adult patients with sickle cell disease (SCD), no consensus or quality efficacy data exist on its use. The Sickle Cell Disease and CardiovAscular Risk- Red cell Exchange (SCD-CARRE) trial tests the hypothesis that an automated chronic RBCX transfusion strategy reduces acute health care encounters and death while improving quality of life and end-organ function (cardiac, pulmonary and renal) in participants with SCD that are at high risk of death. METHODS: Adult patients with SCD with elevated tricuspid regurgitant jet velocity (TRV) and/or chronic kidney disease were considered to be at high risk of death and were randomly assigned to RBCX plus standard of care vs standard of care alone. Participants assigned to RBCX received 12 months of exchange transfusions to maintain target pretransfusion hemoglobin S% < 30%, post-transfusion hemoglobin S% < 20%, and post-transfusion hemoglobin concentration ≥10 g/dL. All study participants were managed according to NHLBI/ASH/ATS Expert Panel guidelines. The primary endpoint was the number of SCD acute health care encounters or death over 13 months. Secondary endpoints included measures of cardiovascular and renal function, exercise capacity, patient reported outcomes (all collected at baseline, and months 4, 8, and 12), and transfusion-related adverse events (collected monthly). RESULTS: Between 2020 and 2025, the SCD-CARRE trial randomized 173 participants at 23 sites across 3 countries. Enrolled participants had mean (SD) age of 45.8 (11.8) years and 54% were female. At baseline, participants had average TRV of 2.8 (0.5) m/s such that 45.9% had a TRV between 2.5 to 2.9 m/sec and 28.1% had a TRV ≥ 3.0 m/sec. The median (Q1, Q3) eGFR in this cohort was 60 (36, 110) mL/min/1.73 m2. The median (Q1, Q3) 6-minute walk test distance was 375 meters (309, 439), the median daily steps were 3,728 (2,187, 5,821), and participants experienced a median (Q1, Q3) of 2 (1, 5) pain episodes in the year prior to randomization. The trial results are pending. CONCLUSIONS: The SCD-CARRE trial successfully enrolled a cohort of n = 173 adults with SCD. This study highlights a rationale to evaluate the effect of automated chronic RBCX transfusion strategy plus standard of care as compared to standard of care alone in SCD patients at high risk of death with a focus on patient centered outcomes, preservation of cardiovascular function, end-organ complications and death. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT04084080, https://clinicaltrials.gov/study/NCT04084080.

Adult↗

PubMed2026

Mitophagy-mediated ferroptosis involved in 2,5-hexanedione-induced neurotoxicity in rats.

n-Hexane, a widespread environmental and industrial pollutant, poses serious health risks, particularly neurotoxicity. Chronic exposure primarily induces sensorimotor neuropathy via its metabolite 2,5-hexanedione (HD), yet the mechanisms underlying HD-induced neuronal injury remain unclear. Recent evidence implicates ferroptosis, an iron-dependent form of regulated cell death, in neurodegenerative processes. In this study, Sprague-Dawley (SD) rats were exposed to HD to establish a neuropathy model. Ferroptosis involvement was assessed using the iron chelator deferoxamine (DFO) and the ferroptosis inhibitor Ferrostatin-1. The potential role of mitophagy in HD-induced ferroptosis was evaluated by monitoring mitophagy markers and by autophagy inhibition with chloroquine (CQ). In vitro, SH-SY5Y cells were transfected with PINK-1 siRNA to explore mitophagy-mediated regulation of ferroptosis. HD exposure led to iron accumulation, lipid peroxidation, mitochondrial abnormalities, and decreased GPX4 in rat spinal neurons. DFO or ferrostatin-1 treatment ameliorated these changes and preserved mitochondrial integrity. Mechanistic analyses revealed HD-induced activation of mitophagy, as shown by upregulation of Beclin-1, LC3II, Drp-1, and PINK-1, with concomitant downregulation of P62 in spinal mitochondria. CQ suppressed mitophagy, reduced iron deposition and lipid peroxidation, and improved motor function. Similarly, PINK-1 knockdown in SH-SY5Y cells mitigated HD-induced mitophagy and ferroptosis. These findings demonstrate that HD induces neuronal ferroptosis via mitophagy activation. Inhibition of ferroptosis or mitophagy effectively attenuates HD-induced neurotoxicity, suggesting potential therapeutic strategies to reduce neural damage from environmental n-hexane exposure.

Animals↗

PubMed2026

Molecular adaptation of caspase genes to salinity stress in the tropical sea cucumber Stichopus monotuberculatus: A comparative analysis across echinoderms.

Apoptosis is an essential physiological process that plays a critical role in development and tissue homeostasis. Caspases, as central regulators of apoptosis, are crucial in controlling inflammation and cell death. In this study, we investigated the caspase gene family in Stichopus monotuberculatus to explore their potential roles in salinity stress adaptation. Five caspase genes were identified from the genome of S. monotuberculatus, including Smcaspase3, Smcaspase6, Smcaspase8a, Smcaspase8b, and Smcaspase8c. Phylogenetic analysis revealed that these Smcaspase genes clustered into distinct caspase subfamilies and showed high conservation with homologs from other echinoderms and representative vertebrates. Conserved motif and gene structure analyses showed relatively similar structural patterns within each clade, whereas divergence was observed among different subfamilies. Promoter analysis identified numerous cis-acting elements related to gene regulation, immune response, and growth and development. Expression profiling under salinity stress showed that Smcaspase8a was significantly upregulated, particularly under prolonged stress, whereas the other genes exhibited limited transcriptional responses. Our findings highlight caspase function in salinity stress and provide the foundation of molecular salinity adaptation mechanisms in S. monotuberculatus.

Animals↗

PubMed2026

Assessing time to symptomatic progression, a patient-relevant efficacy endpoint, in the MARIPOSA study in non-small cell lung cancer.

INTRODUCTION: In the phase 3 randomized MARIPOSA study, amivantamab and lazertinib combination therapy demonstrated improved progression-free survival (PFS) and overall survival (OS) versus osimertinib in participants with previously untreated, epidermal growth factor receptor-mutated advanced non-small cell lung cancer. Time to symptomatic progression (TTSP) was introduced to assess clinical worsening and complement endpoints that investigate radiographic disease progression and patient-reported outcomes. TTSP provides an easily interpretable measure of disease-specific symptom worsening to further support patient experience. METHODS: In MARIPOSA, TTSP was quantitatively assessed as a secondary efficacy endpoint and defined as the time from randomization until participants experience disease-specific symptom worsening requiring a clinical intervention or treatment change, or death. To evaluate the impact of amivantamab and lazertinib on TTSP considering its established OS benefit against osimertinib, an exploratory analysis censoring death events was performed. RESULTS: At the final protocol-specified OS analysis (median follow up: 37.8 months), median TTSP was 43.6 months with amivantamab and lazertinib versus 29.3 months with osimertinib (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.57-0.83; p < 0.0001). Amivantamab and lazertinib reduced deaths following a TTSP event compared to osimertinib. A strong correlation between TTSP and PFS or OS was observed. CONCLUSIONS: Amivantamab and lazertinib significantly delayed TTSP versus osimertinib. TTSP offers a clinician-validated measurement of disease-specific symptom worsening, capturing symptoms perceived by patients that prompt clinical action. TTSP is highly correlated with PFS and OS, providing complementary insights alongside traditional endpoints. TTSP enhances understanding of treatment benefit and supports informed clinical decision-making by integrating patient experience.

Humans↗

PubMed2026

Umbilical Cord-Derived Cell-Based Interventions for Bronchopulmonary Dysplasia and Related Complications in Preterm Infants: A Bayesian Sparse-Data Meta-Analysis.

Bronchopulmonary dysplasia (BPD) is a major complication of prematurity with limited disease-modifying therapies. We evaluated umbilical cord-derived cell-based interventions for BPD and related complications in preterm infants. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020-based systematic review and meta-analysis were registered in PROSPERO. PubMed, Cochrane Library, Web of Science, CNKI, and Wanfang were searched from inception to June 14, 2026. Comparative clinical studies of umbilical cord-derived cell-based interventions in preterm infants at risk of or diagnosed with BPD were included. Outcomes included BPD, BPD severity, death, persistent pulmonary hypertension of the newborn (PPHN), patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), late-onset sepsis (LOS), and adverse events (AEs). Bayesian random-effects meta-analysis used a binomial-normal hierarchical model to estimate pooled odds ratios (ORs), 95% credible intervals (CrIs), prediction intervals, and heterogeneity. Twelve studies were included. Umbilical cord-derived cell-based interventions showed a possible protective effect on overall BPD (OR, 0.48; 95% CrI, 0.14-1.20). Stronger associations were observed for severe BPD (OR, 0.17; 95% CrI, 0.01-0.85), moderate or severe BPD (OR, 0.28; 95% CrI, 0.09-0.70), and ROP stage ≥3 (OR, 0.17; 95% CrI, 0.02-0.65). No conclusive benefit or harm was observed for death, PPHN, PDA, IVH, NEC, or LOS. No treatment-related serious AEs were identified. However, prediction intervals were generally wide, and the certainty of evidence was low to very low for most outcomes. Umbilical cord-derived cell-based interventions may reduce the risk of moderate or severe BPD in preterm infants, with an additional potential benefit for ROP stage ≥3. Current evidence remains limited, and larger randomized trials with standardized outcomes and long-term follow-up are needed.

Humans↗

PubMed2026

Recurrent myocardial infarction identified by centralized troponin review: Insights from the MINT trial.

BACKGROUND: The utility of routine troponin testing to identify recurrent myocardial infarction (MI) after an incident MI is unclear. We assessed the incidence and prognosis of recurrent MIs identified from centralized troponin review in patients from the Myocardial Ischemia and Transfusion (MINT) trial. METHODS: The MINT trial randomized patients with acute MI and anemia to a liberal vs restrictive red blood cell transfusion strategy. Suspected recurrent MIs were identified through both site-report and centralized review of troponin levels collected for 3 days following randomization. Differences in cardiac, noncardiac, and all-cause death at 30 and 180 days were compared across patients with any site-reported MI, only centrally identified MI, and no recurrent MI. RESULTS: Among 3,504 patients, 275 (7.8%) had a recurrent MI within 30 days; 119 (43.3%) by site-report, and 156 (56.7%) by central troponin review only. Rates of cardiac and all-cause death at 30 and 180 days were highest for patients with site-reported MI, intermediate for centrally identified MI, and lowest for no recurrent MI; rates of noncardiac death did not vary. Patients with only centrally identified recurrent MI had an increased risk of cardiac death at 30 days (RR 1.9, 95% CI 1.0-3.4) and 180 days (RR 1.7, 95% CI 1.1-2.7) compared to those without recurrent MI. CONCLUSIONS: In patients with acute MI and anemia, centralized troponin review identified more than half of all recurrent MI events. Patients with centrally identified MI had a higher risk of cardiac death than those with no recurrent MI. TRIAL REGISTRATION: ClinicalTrials.gov NCT02981407 https://clinicaltrials.gov/study/NCT02619136.

Humans↗

PubMed2026

Identification of molecular subtypes in clear cell renal cell carcinoma based on chromatin regulators and tumor immune microenvironment profiling.

In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.

Humans↗

PubMed2026

PPRC1 is a prognostic biomarker and key regulator of mitochondrial oxidative phosphorylation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.

Humans↗

PubMed2026

Suppression of HIV-1 replication in CEM-A cell cultures by trans-splicing group I introns targeting PAS/PBS sequences and conditionally expressing ΔN-Bax.

Anti-HIV group I introns containing antisense guide sequences directed against the HIV-1 primer activation signal and primer-binding site (PAS/PBS) were designed and evaluated. Because PAS/PBS sequences are present in the viral RNA species examined, these RNAs can serve as trans-splicing substrates. The introns were active against both artificial target RNAs and viral RNA generated during infection. Cleavage and degradation of targeted viral RNA may have contributed to suppression, whereas inclusion of a 3' exon encoding the proapoptotic protein ΔN-Bax was associated with increased programmed cell death and may have augmented suppression of viral replication. In cultured CEM-A cells, transgene expression of these introns markedly suppressed HIV-1 replication, with p24 levels falling below the assay detection limit in selected clones. RESULTS: RT-PCR and sequence analysis detected splice products containing the expected PAS/PBS junctions. In the dual-luciferase assay, intron expression reduced normalized Gaussia luciferase signal by approximately 70% relative to the negative control. Qualitative Annexin V imaging and caspase-3 assays were consistent with infection-dependent apoptosis after ΔN-Bax splice-product formation. Transient expression of each intron in HEK293T cells followed by infection with VSV-G-pseudotyped HIV-1NL4-3 at an MOI of 2 reduced p24 levels by approximately 50% at 4 days post-infection. Construct 128L produced the strongest RT-PCR band under the tested conditions and was selected for subsequent experiments. A canonical splice product and a low-abundance noncanonical splice product were detected; both involved the intended HIV-derived target RNA, although transcriptome-wide off-target splicing was not assessed. Heterogeneous transformed HEK293T populations showed an approximately 2-log10 reduction in p24. In selected clonal HEK293T and CEM-A lines, p24 was below the assay detection limit at the measured endpoints, including up to 90 days after infection in some CEM-A clones. CONCLUSIONS: PAS/PBS-targeting group I introns suppressed HIV-1-associated p24 production in the tested cell-culture models. Linking the introns to a ΔN-Bax 3' exon was associated with infection-dependent apoptosis and may further limit viral replication and spread. The use of highly conserved, functionally constrained target sequences may reduce the likelihood of escape, but viral evolution and transcriptome-wide off-target effects were not assessed. This conditional death-upon-infection strategy warrants further evaluation in primary-cell and in vivo models.

Humans↗

PubMed2026

Transcriptomic insights into temperature regulation of proliferation and differentiation in skeletal muscle cells of Nibea albiflora.

Myogenesis involves sequential stages of muscle satellite cell activation, myoblast proliferation, differentiation, and fusion into multinucleated myotubes. Teleost muscle exhibits indeterminate growth and is highly sensitive to environmental temperature, yet the underlying mechanisms by which temperature regulate proliferation and differentiation remain poorly understood. In this study, we established a primary skeletal muscle cell culture from the yellow drum (Nibea albiflora), an economically important marine fish, and integrated morphological observations with comparative transcriptomics analysis to characterize cellular and molecular responses at 28 °C and 20 °C during both proliferation and differentiation stages. Phenotypic analysis revealed that 28 °C significantly enhanced both myoblast proliferation and myogenic differentiation ability compared with 20 °C. Transcriptomic profiling revealed that at 28 °C, differentiation upregulated extracellular matrix(ECM) organization, calcium signaling, and sarcomere assembly, while proliferation enhanced focal adhesion, growth factor signaling, and lipid metabolism. At 20 °C, differentiation was characterized by glutathione metabolism, and ferroptosis, while proliferation involved cytokine-cytokine receptor interaction and negative regulation of signal transduction. Core myogenic regulatory factors (MRFs), particularly myogenin, were strongly upregulated at 28 °C during the differentiation stage, serving as an internal control. Based on these findings, we propose a testable model that elevated temperature coordinates Ca2+-dependent MRF activation with ECM-integrin signaling to drive sarcomere assembly and muscle growth. Key differentially expressed genes (DEGs) regulating myogenesis in N. albiflora were also identified. This study provides a mechanistic framework for temperature adaptation in teleost skeletal muscle and identifies candidate genes for functional validation and marker-assisted selection, as well as a rationale for temperature management strategies to improve aquaculture yield of N. albiflora.

Animals↗

PubMed2026

GSTT1 promotes stemness and FGFR inhibitor sensitivity in pancreatic cancer through regulation of CD133 (PROM1).

Pancreatic ductal adenocarcinoma (PDA) is among the deadliest malignancies, driven by metastatic progression and profound cellular heterogeneity. We previously identified glutathione S-transferase theta 1 (GSTT1) as a regulator of a slow-cycling, highly metastatic tumor cell population, suggesting that GSTT1High cells may possess stem-like properties. Here, we define the functional and molecular features of this subpopulation in metastatic PDA. Using a mCherry-tagged Gstt1 reporter system in metastatic murine PDAC cells, we enriched for Gstt1High cells and observed increased tumor sphere formation, accompanied by upregulation of stemness-associated genes including PROM1 (CD133) and activation of Wnt and FGF signaling pathways. In human PDA models, CD133HighGSTT1High cells exhibited enhanced tumor sphere initiation and expansion compared to other populations, defining a maximal stem-like state. Notably, sensitivity to FGFR inhibitors was observed only under tumor sphere conditions, highlighting a context-dependent therapeutic vulnerability. Mechanistically, FGFR3 expression correlated with GSTT1 and CD133 levels, and FGF signaling was required to sustain this state. GSTT1 knockdown reduced CD133 protein levels, impaired tumor sphere formation, and altered sensitivity to FGFR inhibition. These findings were largely recapitulated in patient-derived PDA organoids, where GSTT1 and PROM1 co-expression predicted increased tumor sphere formation and enhanced response to the multi-kinase inhibitor Nintedanib. Together, these results identify a GSTT1HighCD133High stem-like subpopulation in metastatic PDA and identify an FGFR-dependent signaling axis that sustains this state, representing a potential therapeutic vulnerability.

AC133 Antigen↗

PubMed2026

Role of omentin-1 in the global proteome of porcine pituitary cells: insights into proliferation- and apoptosis-related processes.

The anterior pituitary integrates endocrine regulation, cellular growth, and adaptive responses. Adipokines, secreted mainly by adipose tissue, act as hormonal signals linking metabolism, inflammation, appetite, and reproduction. They regulate hypothalamic-pituitary-ovarian axis by modulating hormone secretion and intracellular signaling. The presence of adipokine receptors in anterior pituitary suggests local metabolic-endocrine interactions. Omentin-1, predominantly expressed in visceral adipose tissue, participates in glucose metabolism and ovarian steroid regulation. Recent findings indicate that omentin-1 modulates tropic hormones, their receptors, and adipokine balance in anterior pituitary cells. We hypothesized that omentin-1 affects protein expression and signaling pathways involved in pituitary cell proliferation and apoptosis. This study examined its effects in anterior pituitary cells from Large White and Meishan pigs. Proteomic analysis identified 230 candidate differentially abundant proteins after omentin-1 treatment: 30 downregulated and 3 upregulated in Large White pigs, and 107 downregulated and 90 upregulated in Meishan pigs, associated with enriched 116 Gene Ontology terms. Key proteins were associated with cell cycle, DNA replication, gene expression, and posttranscriptional/posttranslational regulation. Responses differed between breeds. CDK5RAP2 and SIX1 were linked to proliferative control in Large White pigs, whereas AKT1S1 and RHOA were among the proteins associated with the broader proteomic response observed in Meishan pigs. Meishan pigs showed dynamic apoptotic protein regulation, including HTRA2, PARP2, and DFFA. Complementary in vitro experiments demonstrated that omentin-1 downregulated cyclins and caspase-3, upregulated BCL2, increased BCL2/BAX ratio, and modulated ERK1/2, AKT, AMPKα, and STAT3 phosphorylation. Together, these findings suggest that omentin-1 modulates proteomic networks and intracellular signaling associated with anterior pituitary cell function during the mid-luteal phase of the estrous cycle.

Animals↗