Programmed cell death (PCD) encompasses multiple regulated processes, including apoptosis, pyroptosis, ferroptosis, and necroptosis. These pathways form an interconnected network that contributes to the pathogenesis of cardiovascular diseases (CVDs), including atherosclerosis and myocardial ischemia-reperfusion injury. This review highlights cell-type-specific PCD signatures, showing that endothelial cells predominantly undergo pyroptosis and ferroptosis, whereas macrophages exhibit multiple PCD modalities and complex pathological crosstalk. Moreover, the review systematically summarizes key regulatory pathways (e.g., Piezo1 [Piezo-type mechanosensitive ion channel component 1]/NLRP3 [NOD-like receptor family pyrin domain containing 3], and Nrf2 [nuclear factor erythroid 2-related factor 2]/HO-1 [heme oxygenase 1]/GPX4 [glutathione peroxidase 4]), as well as multi-target natural compounds (e.g., melatonin and Guizhitongluo Tablet) that show translational promise and advantages in modulating PCD networks. The review also provides critical insights into major bottlenecks in clinical translation, including nonspecific tissue distribution and the lack of pathway-specific biomarkers. Novel solutions, such as cardiomyocyte-specific delivery systems (e.g., CD47-targeted lipid nanoparticles) and validated biomarkers (prostaglandin-endoperoxide synthase 2 [PTGS2] for ferroptosis), are also proposed. Overall, this review advances our understanding of PCD network regulation in CVDs and proposes innovative precision therapeutic strategies that align with the evolving needs of cardiovascular translational medicine.
Sepsis is characterized by potentially fatal organ failure resulting from the host's abnormal response to infection. Due to the complex and rapid progression of sepsis, timely diagnosis and intervention are required to improve patient prognosis. Copper-dependent cell death, known as "cuproptosis," is a newly discovered mode of cell death that relies on copper. Senescence refers to a state of irreversible cessation of cell division. Both processes play significant roles in various diseases. However, the roles of genes related to cuproptosis and senescence in the pathogenesis of sepsis remain insufficiently understood. In this study, we utilized bioinformatics techniques to explore the involvement of copper-dependent cell death and its connections to sepsis and cellular senescence. We obtained 3 sepsis datasets (GSE28750, GSE54514, and GSE131761) from the Gene Expression Omnibus database and classified the raw data using R packages (R Foundation for Statistical Computing). Copper death- and aging-related genes were manually screened, and differentially expressed cuproptosis and cellular senescence-related differentially expressed genes associated with sepsis were identified. Subsequently, enrichment analysis was applied, and key genes were screened using machine learning techniques for the construction and validation of a sepsis diagnostic model. We then constructed mRNA-miRNA and mRNA-transcription factors interaction networks for the key genes, followed by differential gene analysis, immune infiltration, and enrichment analysis. We identified 17 cuproptosis and cellular senescence-related differentially expressed genes and performed gene enrichment analysis. Subsequently, using least absolute shrinkage and selection operator regression analysis and random forest algorithm, we identified sepsis-related cuproptosis and senescence-associated differentially expressed genes. After taking the intersection, we obtained 11 key genes. Next, through immune infiltration analysis, we found a positive correlation between pyruvate dehydrogenase E1 subunit beta (PDHB) and central memory cluster of differentiation 4 (CD4) T cells, glutaminase and activated CD8 T cells, as well as prion protein, PDHB, and monocytic lineage. There was a negative correlation between PDHB and type 17 T helper cells, amyloid beta precursor protein and activated CD8 T cells, PDHB and neutrophils, and CD274 and B lineage cells. These results suggest that cuproptosis may promote the development of sepsis by affecting the immune system and metabolic functions, providing new insights into the potential pathogenic mechanisms and therapeutic targets of sepsis.
Marginal zone lymphoma (MZL) is a rare non-Hodgkin lymphoma. We recently reported that treatment with ibrutinib-venetoclax under the phase 2 AIM study resulted in an overall response rate of 79%. In the current study, we analyzed the immunology of MZL and the effect of ibrutinib-venetoclax treatment. Peripheral blood mononuclear cell samples from 14 patients with relapsed/refractory MZL were collected over 2 years as part of a preplanned analysis. Immune profile was assessed using spectral flow cytometry and functional assays and compared to age-matched healthy donors. Results were correlated with centrally determined positron emission tomography/computed tomography response. Patients with MZL exhibited normal proportions of monocytes, myeloid-derived suppressor cells, and myeloid dendritic cells, with reduced proportions of plasmacytoid dendritic cells (P < .01). Although there was no difference in total proportions of CD4 or CD8 T cells or natural killer (NK) cells at baseline, there was skewing of memory subsets with upregulation of programmed cell death 1 protein (PD-1) on T cells and TIM3 on NK cells. T-cell production of interferon gamma, tumor necrosis factor α, and CD107a was increased sixfold (P < .001), which did not reduce with treatment. Mature NK cell degranulation was elevated at baseline (P < .05) and decreased with treatment. Complete response to treatment was associated with maintenance or expansion of TIM3+ mature NK cells (P < .05). To our knowledge, this is the first study to examine peripheral blood immunology in MZL as a single disease group. Given the lack of T-cell repair, immunotherapy protocols using ibrutinib may be less effective in MZL. This trial was registered at www.clinicaltrials.gov as #NCT02471391.
Primary mitochondrial diseases (PMD) have limited disease-modifying therapies, currently applicable to only 3 of over 400 discrete gene disorders. Cycloheximide (CHX) is a global cytosolic translation inhibitor we previously reported to rescue PMD preclinical models, although its toxicity precluded clinical development. To identify specific mediators underlying CHX treatment benefit in PMD, SOMAscan-based proteomics was performed in complex I deficient and genetic disease fibroblast cell line models grown in galactose. Thrombopoietin (THPO) and insulin-like growth factor binding protein 5 (IGFBP5) were the only two differentially regulated proteins, together with ERK/MAPK pathway dysregulation, identified upon CHX treatment in PMD versus healthy control cells. THPO inhibition by siRNA or pharmacologic approaches rescued stress-induced viability loss in patient fibroblasts having diverse PMD gene etiologies, and significantly improved mitochondrial stress, linear growth, and neuromuscular function in a classical ndufs2 -/- C. elegans model. IGFBP5 overexpression by lentiviral or mRNA approaches rescued cell viability across distinct PMD gene etiologies, as did IGF1 pharmacologic inhibition across both PMD mutant and C. elegans models. MAPK pharmacologic inhibition rescued multiple distinct complex I disease cells' survival, as well as mitochondrial stress in SLC25A46 -/- C. elegans . Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and C. elegans models. Additionally, single or combined pharmacologic inhibition of THPO or IGF1 significantly enhanced primary and metastatic osteosarcoma cell death. Collectively, targeted small molecule and genetic modulation of THPO, IGF1, or MAPK recapitulated the significant therapeutic benefit of CHX in PMD, while avoiding global translation inhibition. These novel PMD therapies likely confer benefit by attenuating MAPK-driven autophagy and potentially promoting noncanonical glucose uptake, improving cellular energy balance. Overall, these glucose signaling cellular pathway targets hold broad therapeutic promise for PMD patients, warranting further clinical research development.
Mycobacterium avium complex lung disease (MAC-LD) is increasing worldwide. Exosomal programmed death-ligand 1 (PD-L1) has been scarcely investigated in MAC-LD. Plasma exosomes and their PD-L1 from MAC-LD patients and healthy controls were measured and used for co-culturing Jurkat cells with or without PD-L1/PD-1 blocking antibodies. MAC-infected mice were treated with exosome inhibitors to assess exosomal PD-L1 and bacterial burden. Plasma exosomal PD-L1 levels were significantly higher in MAC-LD patients (1,477±1,243 pg/mL) vs. controls (183.8±113.9 pg/mL; P < .001), correlated with cavitary disease (2,415±1,309 vs. 844.1±652.2 pg/mL; P = .008) and decreased after treatment (1,474±961.3 vs. 738.5±820.4 pg/mL; P = .03). MAC-infected macrophage exosomes decreased Jurkat cell survival (72.9±11.5% vs. 98.2±0.6%; P < .01), which could be reversed by PD-L1/PD-1 antibodies. In the mouse study, GW4869 (an exosome biogenesis inhibitor) reduced lung exosomal PD-L1 (497.6±123.1 to 197.7±116.4 pg/mL; P = .008) and bacterial load (996,400±96,316 to 116,400±18,528 CFU; P = .008), whereas DMA (an exosome release inhibitor) showed no significant effect on lung exosome and bacterial load. Exosomal PD-L1 promotes immune suppression and reflects disease severity in MAC-LD. Inhibition of exosome biogenesis reduced exosomal PD-L1 levels and MAC burden in lung, supporting a potential therapeutic avenue that requires further validation.
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, plays a crucial role in tumor progression and immune regulation. We integrated single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic data to identify ferroptosis-active cellular subpopulations within the ESCC tumor microenvironment. A ferroptosis-related prognostic model was constructed using LASSO-Cox regression and validated across independent cohorts from TCGA and GEO. Associations with immune infiltration, tumor mutation burden, therapeutic response, and drug sensitivity were explored. Furthermore, functional experiments were conducted in vitro using the ESCC cell lines, and the four prognostic core genes were revalidated using an independent single-cell dataset, which was also fully confirmed in clinical ESCC tissue samples. In addition, Western blot analysis was performed to examine the expression levels of ferroptosis-related proteins following CDCA3 knockdown, and to further investigate the impact of CDCA3 depletion on the cellular response to the ferroptosis inducer RSL3. Four ferroptosis-related genes (CBS, CDCA3, GALNT14, and IDO1) were identified used to construct a robust risk model, effectively stratifying patients into high- and low-risk groups with significant differences in survival, immune infiltration, and predicted treatment response. In vitro experiments confirmed that CDCA3 knockdown significantly inhibited the proliferation and migration of ESCC cells and induced ferroptosis. GSE188900 single-cell sequencing data further confirmed that the aforementioned genes were significantly upregulated at single-cell resolution in tumor cells, with consistent validation in clinical ESCC tissue samples, Moreover,experimental results showed that knockdown of CDCA3 lead to the downregulation of ferroptosis inhibitor-related genes and upregulation of ferroptosis-promoting genes, thereby enhancing the sensitivity to RSL3-induced ferroptosis. Our study presents a single-cell-resolved ferroptosis gene signature with strong prognostic and therapeutic implications for ESCC. The signature was validated in clinical tissue samples, and this model lays the foundation for ferroptosis-targeted therapeutic strategies.
Doxorubicin (DOX) is a potent anthracycline chemotherapeutic agent whose clinical utility is significantly constrained by severe side effects, most notably DOX-induced cardiotoxicity (DIC). Pathophysiological mechanisms of DIC include oxidative stress, mitochondrial dysfunction, programmed cell death, and inflammation. Given the therapeutic potential of stem cell technology, this narrative review aims to summarize current evidence regarding the use of various stem cell types, particularly mesenchymal stem cells (MSCs), as a potential treatment for DIC. This study conducted a comprehensive review of the literature concerning stem cell-based therapies in the context of DIC. We evaluated evidence regarding both pluripotent stem cells (including embryonic and induced pluripotent stem cells) and multipotent adult stem cells (such as bone marrow, adipose, and umbilical cord-derived MSCs) to assess their role in mitigating DOX-induced cardiac damage. Current research indicates that stem cells, particularly MSCs, possess significant regenerative capabilities that may counteract the multifaceted pathophysiology of DIC. Evidence suggests that these cells can modulate inflammatory responses, alleviate oxidative stress, and support mitochondrial repair in damaged cardiac tissue, thereby offering a promising strategy to protect against or reverse chemotherapy-induced heart injury. Stem cell-based therapy represents a promising and innovative frontier for the management of DOX-induced cardiotoxicity. While preclinical and emerging data highlight the therapeutic potential of MSCs in cardiac protection, further standardized research is required to fully elucidate their mechanisms and ensure clinical safety and efficacy for patients undergoing chemotherapy.
Cf resistance proteins of tomato that provide resistance against the extracellular fungal pathogen Fulvia fulva are receptor-like proteins (RLPs) localized at the cell surface. As they lack a cytoplasmic kinase domain, Cf proteins require 2 co-receptors to activate downstream immune responses. In the resting state, Cf proteins constitutively interact with the receptor-like kinase (RLK) SUPPRESSOR OF BIR1-1 (SOBIR1), whereas upon recognition of the matching avirulence (Avr) effector, the RLK BRI1-ASSOCIATED KINASE 1 (BAK1) is recruited. Cf proteins have a typical leucine-rich repeat (LRR)-RLP structure, consisting of an LRR ectodomain, a transmembrane domain, and an intracellular juxtamembrane domain that is referred to as the C-terminal tail. Cf-4 and Cf-9 have identical C-terminal tails, while the C-terminal tails of Cf-2 and Cf-5 differ by a single amino acid. Interestingly, the Cf-5/Avr5- and Cf-2/Avr2-triggered immune response results in a slower and weaker hypersensitive response (HR)-related cell death than the response triggered by Cf-4/Avr4 and Cf-9/Avr9. Domain swapping between Cf-5 and Cf-9 revealed that the C-terminal tail plays a specific role in determining the intensity of the immune response. Notably, the pool of SOBIR1-associated Cf-4 and Cf-9 proteins is much larger than that of Cf-2 and Cf-5, and a full-length C-terminal tail is required for immune signaling activation. This work provides a basis for further studies on RLP engineering to enhance crop resistance against detrimental pathogens.
While somatic mitochondrial dysfunction occurs in diverse cancers, the association between oncogenesis and germline mitochondrial gene pathogenic variants remains unclear. Further, few clinical observations have been reported of cancer occurring in primary mitochondrial disease (PMD) patients. To improve understanding of the potential modulating role for PMD gene disorders in cancer prevalence. 727 individuals, including 100 with PMD, from 97 unrelated families were retrospectively surveyed to assess their history of individual cancer occurrence. We evaluated survey responses by characterizing the cancer prevalence among the study cohort and comparing to the general U.S. population via the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database. Odds ratio calculation was performed to determine the association of survey responses and cancer prevalence. Although overall cancer prevalence in PMD probands and their families was elevated compared to the NCI SEER rate (8800 vs 5600 cases per 100,000), odds ratio calculation determined that PMD did not significantly increase the likelihood of developing cancer, with a non-significant trend observed toward less cancer occuring in PMD that needs to be explored in further studies. Cancer prevalence was significantly correlated with advanced age. Significantly reduced prevalence of prostate cancer was seen across the entire cohort. Surprisingly, while low absolute prevalence (n = 3), a 9-fold increased odds ratio of cancer was seen in POLG patients relative to those with other causes of PMD. No evidence of increased cancer odds was identified in a cohort of PMD patients and their close relatives. Interestingly, a possible inverse association, which did not reach statistical significance, was suggested between mitochondrial disease status and cancer odds. Future prospective investigations in larger PMD kindreds are warranted to validate and evaluate potential mechanistic relations between cancer prevalence and PMD. No increased odds ratio but rather a non-significant trend toward inverse relationship between cancer and primary mitochondrial disease was observed in a retrospective cohort survey study, based on which future studies are warranted. Mitochondria are key organelles in our cells that make energy, help control cell death, and regulate the production of reactive oxygen species. Because of these roles, scientists have long suspected that mitochondrial dysfunction might influence cancer development. Tumors often show abnormal mitochondrial activity, but it is unknown whether people who are born with inherited mitochondrial disorders—called primary mitochondrial diseases (PMD)—are more or less likely to develop cancer. PMD includes many different inherited conditions caused by gene changes in either mitochondrial or nuclear DNA. Although cancer cells often acquire mitochondrial mutations, inherited mitochondrial gene changes that impair mitochondrial energy production in the respiratory chain have not been shown to strongly increase cancer odds. To explore this question, we collected health information from 727 individuals across 97 families, including 100 people with PMD. We compared how often cancer occurred in these families to cancer rates from the National Cancer Institute. We also observed whether having PMD, carrying a PMD disease gene variant, or relation to someone with PMD affected a person’s likelihood of developing cancer. A higher overall cancer prevalence was seen in PMD families compared to the general population that appeared attributable to advanced age, as older adults had higher cancer rates regardless of PMD status. Importantly, PMD status did not increase the likelihood of developing cancer. Rather a non-significant trend was observed toward a negative association. One surprising exception was that individuals with POLG-related PMD showed a higher odds ratio of cancer compared to those with other PMD types, although the affected patient number was small and absolute prevalence remained low. Collectively, these results did not reveal a statistically significant association between primary mitochondrial disease and cancer prevalence. Larger studies are needed to confirm these findings and understand whether and how inherited mitochondrial dysfunction might influence cancer development.
Acetate is the metabolic precursor of acetyl-coenzyme A (CoA), fuelling histone acetylation. We aimed to investigate whether the acetate-acetylation axis is hijacked in tumour endothelial cells (TECs) to govern hepatocellular carcinoma (HCC) progression. The endothelial acetate-acetylation axis and its impact on malignant phenotypes and anticancer therapy were systematically dissected using clinical specimens, primary endothelial cells (ECs) from HCC (tumour endothelial cells, TECs) or non-tumour liver tissues (non-tumour endothelial cells, NECs), EC lines and diverse mouse models. Compared with NECs, TECs showed elevation of acetate transporter (monocarboxylate transporter 1, MCT1), metabolic enzyme ACSS2 and H3K27ac. Acetate was highly enriched within tumour and surrounding parenchyma, and correlated positively with tumour angiogenesis. Functionally, acetate or hepatoma-conditioned media increased endothelial H3K27ac and EC migration, which were attenuated by inhibiting MCT1 or ACSS2. Notably, acetate-treated ECs, but not acetate alone, drived CD8+ T cell exhaustion and regulatory T cell (Treg) expansion. In mouse hepatoma allograft models, acetate administration increased H3K27ac levels in TECs, driving angiogenesis, tumour growth and metastasis, while reducing CD8+ T cells and expanding Tregs. Mechanistically, acetate orchestrated pro-angiogenic and immunosuppressive transcriptional programmes in ECs via histone acetylation. Therapeutically, pharmacological ACSS2 inhibition, EC-targeting simACSS2-liposomes and adeno-associated virus (AAV)-TIE2-shmACSS2 all decreased H3K27ac levels in TECs, inhibited angiogenesis, increased CD8+ T cells and reduced Tregs. Crucially, ACSS2 inhibition synergised with anti-programmed cell death protein 1 (PD-1) to alleviate immunosuppression, curb angiogenesis and suppress tumour progression. Hepatic acetate accumulation and concomitant MCT1/ACSS2 upregulation in TECs drives endothelial epigenetic remodelling, thus fuelling angiogenesis, immunosuppression and HCC progression. Targeting this metabolic-epigenetic axis represents a novel approach to potentiate HCC therapy and sensitise immunotherapy.
This study aims to investigate the action mechanism and target molecules of the ultrafiltration membrane extract of Angelicae Sinensis Radix and Hedysari Radix in improving renal tissue injury in rats with diabetic kidney disease(DKD) from the perspective of mitochondrial function. Ten SPF-grade male Wistar rats were selected as the control group, while 40 rats were fed a high-fat and high-sugar diet for four weeks followed by a single intraperitoneal injection of streptozotocin(STZ) 35 mg·kg~(-1) to establish the DKD model. The successfully modeled rats were then randomly divided into four groups: the model group, the canagliflozin group, the Angelicae Sinensis Radix and Hedysari Radix aqueous decoction group, and the ultrafiltration membrane extract of Angelicae Sinensis Radix and Hedysari Radix group, with ten rats per group. All groups were administered via gavage for eight weeks. Renal function was assessed through 24 h urinary total protein(24-UTP) and biochemical parameters. HE staining, TUNEL staining, and transmission electron microscope were used to observe pathological morphological changes, apoptosis, and the status of intracellular organelles in cells. ELISA and Western blot were employed to measure adenosine triphosphate(ATP) content and the expression of mitochondrial function-related proteins, including optic atrophy 1(OPA1), mitofusin 2(Mfn2), dynamin-related protein 1(Drp1), ubiquitin-binding protein P62(P62), B-cell lymphoma/leukemia-2(Bcl-2), Bcl-2 interacting protein1(Beclin-1), and Bcl-2-associated X protein(Bax) in renal tissue. The results show that, compared to those in the control group, the rats in the model group exhibit a significant decrease in body weight(P<0.01), along with elevated levels of blood glucose, 24-UTP, blood urea nitrogen(BUN), and serum creatinine(Scr)(P<0.01). Renal tubular dilation, vacuolar changes in renal tissue cells, and a significant increase in apoptosis rate(P<0.01) are observed, accompanied by mitochondrial swelling, cristae disappearance, and rupture. ATP levels in renal tissue are significantly reduced(P<0.01), while the protein expressions of OPA1, Mfn2, Drp1, Beclin-1, and Bax are significantly increased(P<0.05, P<0.01). The expression levels of P62 and Bcl-2 are significantly decreased(P<0.01). Compared to those in the model group, the rats in the ultrafiltration membrane extract group show an upward trend in body weight, with reductions in 24-UTP, BUN, and Scr levels(P<0.01). Renal tubular dilation and glomerular cell vacuolation are alleviated, and the apoptosis rate of renal tissue cells is significantly reduced(P<0.01). Mitochondria exhibit mild swelling but remain largely intact. ATP levels in renal tissue are significantly increased(P<0.01), while the expressions of OPA1, Mfn2, Drp1, Beclin-1, and Bax are significantly decreased(P<0.01). The expression of Bcl-2 is significantly increased(P<0.01). In conclusion, ultrafiltration membrane extract of Angelicae Sinensis Radix and Hedysari Radix may attenuate renal tissue injury and delay disease progression in DKD rats by restoring mitochondrial dynamics, controlling mitochondrial fission-fusion balance, and improving mitochondrial function.
Ischemic stroke (IS) currently lacks well-characterized peripheral-blood biomarkers that capture early, pathway-level biology. Programmed cell death (PCD) pathways may shape post-stroke neuroinflammation and could yield clinically informative transcriptional signatures. Public cohorts (GSE16561 discovery; GSE58294 external test) were analyzed. We quantified sample-level pan-PCD activity using ssGSEA based on a curated PCD gene set,identified PCD-associated modules via WGCNA, and intersected with limma-derived DEGs. Two complementary machine learning (LASSO and SVM-RFE) were used to select compact candidate biomarkers. Diagnostic performance was evaluated by ROC analysis. Immune infiltration was inferred by ssGSEA (28 immune signatures) and correlated with candidate genes. Drug candidates were prioritized using Enrichr/DSigDB and explored by molecular docking. In vivo validation in a rat MCAO model was additionally performed at the brain-tissue level. A pan-PCD score was higher in IS than controls and guided WGCNA to a PCD-associated module. Intersection with DEGs yielded 58 PCD-related genes. LASSO and SVM-RFE converged on three biomarkers-CREBBP, ANTXR2, and ARG1. These genes showed consistent discriminative performance in both discovery (AUCs: 0.937-0.981) and external test cohorts (AUCs: 0.656-0.931) and were associated with neutrophil-skewed immune infiltration. In vivo validation in a rat MCAO model confirmed upregulation of all three genes in ischemic brain tissue. Enrichr/DSigDB prioritization and docking highlighted papaverine (CREBBP) and trichostatin A (ANTXR2) as plausible leads. An integrative network-ML framework delineated a peripheral-blood pan-PCD-related transcriptional pattern in IS and prioritized three biomarkers with consistent diagnostic performance and a neutrophil-skewed immune context. The exploratory pathway-gene-drug framework proposed here nominates testable compounds and provides a basis for prospective multi-cohort validation and mechanistic studies.
Systemic anticancer therapy (SACT) near the end of life among patients with metastatic non-small cell lung cancer (NSCLC) is considered a population-level quality indicator of potentially inappropriate end-of-life care. We investigated factors associated with SACT in the final 6 weeks of life among patients diagnosed with metastatic NSCLC to optimise end-of-life care. A multicentre retrospective cohort study was conducted among patients with metastatic NSCLC across 7 hospitals in the Dutch Santeon network. Data were extracted from electronic health records. The primary outcome was the receipt of SACT (immunotherapy and/or chemotherapy) within 6 weeks before death. Variables included relevant demographics, clinical and tumour characteristics, palliative care team involvement, emergency department (ED) visits, and hospitalisations. A multivariable logistic regression with backward selection was employed to identify associated variables. Among 365 included patients, 37 % received SACT in the last 6 weeks of life. Notably, these patients were significantly more likely to die in a hospital (44.1 % vs 9.6 %), to visit the emergency department (77.9 % vs 32.8 %) or to be hospitalised in the last 6 weeks of life (80.1 % vs 37.1 %). Hospitalisations before last treatment were independently associated with SACT use in the last 6 weeks of life (OR 2.673 (CI 1.317-5.427), p = 0.006) whereas ED visits were retained in the final model but were not statistically significant (OR 1.688, 95 % CI 0.861-3.311; p = 0.128). This study highlights the importance of better understanding potentially inappropriate care near the end of life among patients with metastatic NSCLC, specifically when focusing on previous hospitalisations or emergency department visits.
Transcription is essential for cellular stress response. However, how RNAPII respond to and are regulated during stress are poorly understood. We show that RNAPII is degraded during many types of cellular stresses. In osmotic stressed cells, the TNFα-p38 pathway was activated and promoted the neddylation of the CUL1 E3 ligase complex, which interacted with RPB1 through FBXO11 to ubiquitylate and degrade RNAPII. This caused genome wide RNAPII binding reduction, but prevented RNAPII binding loss from genes with low promoter GC content. This redistribution protected the RNAPII loss from stress response genes in the cell adhesion, MAPK and GPCR pathways. RNAPII redistribution is vital for cell survival, as degradation blockage resulted in the loss of RNAPII from low GC promoters and compromised stress response from disrupted cell adhesion to increased apoptosis. Thus, rapid RNAPII degradation and RNAPII redistribution are components of the cellular stress response to benefit cell survival.
To identify shared molecular mechanisms and crosstalk genes (CGs) between diffuse large B-cell lymphoma (DLBCL) and primary Sjögren's syndrome (PSS), and to explore the role of MICA in the immune microenvironment (IME). Bioinformatics analysis of GEO datasets identified differentially expressed genes (DEGs). Enrichment, immune infiltration, and Mendelian randomization analyses were performed. Diagnostic biomarkers were screened using Lasso regression. Functional roles of MICA were validated in SUDHL-6 cells via overexpression/knockdown, assessing immune cell infiltration, cytokine secretion, proliferation, and apoptosis. We identified 50 shared DEGs. RPL31, HNMT, and IFI27 were defined as diagnostic biomarkers. MR analysis confirmed a causal effect of PSS on DLBCL risk. MICA interacted with RPL31 and HNMT. MICA overexpression enhanced CD8+ T-cell infiltration and activation, elevated pro-inflammatory cytokine release, suppressed tumor cell proliferation, and promoted apoptosis. Conversely, MICA knockdown suppressed anti-tumor immune activity and promoted tumor growth. MICA plays a key role in shaping the immune microenvironment of DLBCL and PSS. By reinforcing anti-tumor immune responses and limiting tumor growth, it emerges as a promising biomarker and therapeutic target in both diseases.
Breast cancer progression and resistance to therapy are strongly influenced by immune evasion within the tumor microenvironment. Immune checkpoint signaling is a major mechanism by which cancer cells evade immune surveillance, thereby promoting tumor progression and reducing the effectiveness of immunotherapy. Recent evidence suggests that extracellular vesicles (EVs) are important mediators of communication between tumor, stromal, and immune cells, enabling the transfer of proteins, nucleic acids, lipids, and other bioactive molecules that regulate immune responses. This review discusses current knowledge on the role of EVs in immune checkpoint regulation in breast cancer, with an emphasis on both programmed death-ligand 1 (PD-L1)-dependent and additional immunosuppressive pathways that collectively contribute to immune escape. A literature review was conducted using PubMed, Google Scholar, and Web of Science, focusing on studies from the past decade related to EV biology, immune checkpoints, and breast cancer. Findings from multiple studies indicate that tumor-derived EVs contribute to immunosuppression by impairing T-cell function, promoting immune tolerance, facilitating metastatic progression, and supporting resistance to immunotherapy. Importantly, EV-mediated effects are different for the breast cancer subtypes, which may play a role in treatment response, disease progression, and clinical outcomes. EVs also show potential as minimally invasive biomarkers for disease monitoring and as therapeutic targets or delivery systems for precision medicine. Overall, this review highlights current evidence on EV-mediated immune checkpoint regulation in breast cancer, highlighting PD-L1 and CTLA-4associated mechanisms as key drivers of immune evasion and promising targets for precision immunotherapy.
Circulating tumor antigens (ctA; tumor markers) are blood-based proteins that can offer prognostic value in non-small cell lung cancer (NSCLC) and may serve as potential early surrogates for survival. Given the significantly reduced testing time and cost of ctA compared with circulating tumor DNA (ctDNA), we further explored the utility of ctA using samples collected from over 2,300 patients participating in five clinical trials (IMpower130, 131, 132, 150, and 110). We analyzed a panel of six ctA (CA125 (cancer antigen 125), CEA (carcinoembryonic antigen), Cyfra21-1 (cytokeratin 19 fragment 21-1; CYFRA), NSE (neuron-specific enolase), SCC (squamous cell carcinoma antigen), and ProGRP (progastrin-releasing peptide)) and CRP (C-reactive protein) from the serum of patients with metastatic NSCLC in these trials, which investigated combinations of atezolizumab (anti-programmed death-ligand 1)±bevacizumab±chemotherapy. Previous work showed that an optimized cut-off using two ctA or a machine learning (ML) model of ctDNA features, both taken at 6 weeks, can stratify patients with stable disease (SD) for survival risk in IMpower150. Building on this approach, we applied an ML model combining ctA features at baseline and at 6 weeks, trained across a much larger aggregate dataset from multiple clinical studies. Previous findings from ctA analysis of IMpower150 were confirmed and found to be applicable to several other trials analyzed in this study. We found that ML model predictions provided similar prognostic performance (c-index of 0.73 and 0.71 in squamous and non-squamous test datasets, respectively), with CYFRA being the top feature for both histologies. While ctA demonstrated limited potential in differentiating treatment effects to inform early drug development, deriving an optimal prediction cut-off for 1-year overall survival (OS) showed that ctA model predictions could effectively stratify patients by radiographic response with 61% sensitivity and 78% specificity, adding significant prognostic value to radiographic imaging. Patients with partial response (PR), progressive disease (PD), or stable disease (SD) at either 6 weeks of treatment or best confirmed overall response could be separated into low-risk or high-risk groups for OS.
Tasisulam, an acyl-sulfonamide compound, is being investigated in clinical trials for the treatment of several malignancies, including non-small cell lung cancer, lymphoma, breast cancer, melanoma, ovarian cancer, colon cancer, and other solid tumors, by promoting apoptosis. However, anemia is among the adverse consequences of tasisulam therapy and is potentially caused by increased eryptosis or premature erythrocyte senescence, characterized by cell contraction and phosphatidylserine (PS) translocation. Underlying signals associated with eryptosis include increased intercellular calcium activity ([Ca2+]i), oxidative stress, excess ceramide production, and stimulation of various kinases (protein kinase C, p38 kinase, casein kinase-1, etc.) or caspases. This research investigated the potential of tasisulam to induce eryptosis and its underlying signaling pathways. Human erythrocytes (0.4%) were incubated with 75, 150, or 300 μg/ml tasisulam for 48 h at 37°C. Flow cytometry revealed that tasisulam (≥300 μg/ml) significantly increased erythrocyte apoptosis, [Ca2+]i, reactive oxygen species (ROS), and ceramide formation without causing cell membrane shrinkage. The effect of tasisulam on erythrocyte death was significantly reduced by the removal of extracellular calcium or the inhibition of casein kinase. In conclusion, tasisulam triggers eryptosis by stimulating calcium influx, ceramide generation, oxidative stress, and casein kinase 1 activation, which may be associated with tasisulam-associated anemia.
Age-related macular degeneration (AMD) is a fundus oculi disease that progressively impairs the central vision of patients. To date, its pathogenesis has not been fully elucidated, and therapeutic options for dry AMD remain limited. Recently, chronic low-grade inflammation has been recognized as an important pathogenic factor in various neurodegenerative diseases, including AMD. The NLRP3 inflammasome, a key component of the innate immune system, has emerged as a critical integrator of retinal stress signals. This review first delineates the molecular architecture and activation modalities of the NLRP3 inflammasome, encompassing canonical, noncanonical, and alternative pathways, as well as its downstream cell death programs, with a particular focus on pyroptosis and PANoptosis. We describe how AMD-associated danger signals converge on NLRP3 inflammasome activation within distinct retinal cell populations and discuss how cell-type-specific NLRP3 responses differently shape retinal homeostasis, degeneration, and neovascularization. We further summarize current evidence indicating that the pathological consequences of NLRP3 activation vary across AMD progression, from amplification of chronic inflammation in early and intermediate AMD to promotion of retinal atrophy in geographic atrophy and angiogenic signaling in neovascular AMD. Finally, we evaluate emerging therapeutic strategies targeting the NLRP3 pathway and discuss the major translational challenges related to cell-type and disease-stage specificity, retinal delivery, and long-term safety. By integrating retinal triggers, cellular responses, senescence-associated inflammation, inflammatory cell death, disease phenotypes, and therapeutic opportunities into a unified framework, this review provides a comprehensive perspective on the role of NLRP3 inflammasome signaling in AMD pathogenesis and treatment.
Fabry disease (FD) is a congenital metabolic disorder characterized by the accumulation of globotriaosylceramide (Gb3) due to deficient alpha-galactosidase A (GLA) activity. Although the presence of urinary mulberry bodies (uMBs) in FD is well documented, their precise origins and molecular composition remain poorly understood. In the present study, we performed comprehensive morphological, molecular, pathological, and structural analyses of uMBs. Our results revealed that uMBs are dynamic structures that exhibit substantial structural plasticity in response to fluid flow. We demonstrated that uMBs originate from podocytes rather than renal tubular cells and are primarily composed of lysosome-derived structures. Furthermore, we identified glomerular basement membrane components within these podocyte-derived uMBs, suggesting a complex shedding process in the urine. Three-dimensional reconstruction with confocal laser scanning microscopy was used to successfully visualize the complex internal architectures of these structures. Experiments using GLA knockout cells suggested a potential association between Gb3 accumulation and the induction of cell death via the JNK signaling pathway. These findings provide novel insights into the structural characteristics and pathological relevance of uMBs in the pathogenesis of FD nephropathy.