Cell Death Discovery最新文献

The skin barrier is crucial for protecting against environmental challenges, preventing water loss, and regulating immune responses. This study aims to investigate the roles and mechanisms of SERPINB7 in skin barrier maintenance. We found that SERPINB7 deficiency disrupts tight junctions of keratinocytes in vitro, and specific knockout of Serpinb7 in keratinocytes impairs skin barrier function in vivo. SERPINB7 deficiency leads to reduced expression of O-GalNAc regulatory proteins and structural abnormalities in the Golgi apparatus, ultimately impairing protein O-GalNAc glycosylation. Legumain acts as a critical mediator in the maintenance of normal biological functions and O-GalNAc glycosylation regulated by SERPINB7. O-GalNAc inhibition exhibits biological effects analogous to those induced by SERPINB7 deficiency, leading to weakened tight junctions, reduced cell adhesion, and compromised skin barrier integrity in keratinocytes and mouse skin, respectively. Consequently, O-GalNAc deficiency exacerbates inflammatory skin diseases such as psoriasis and atopic dermatitis. Mechanistically, O-GalNAc deficiency primarily affects the glycosylation of calcium-related and cell adhesion-related proteins, disrupting calcium signaling and compromising cell adhesion, ultimately leading to skin barrier dysfunction. In summary, this study demonstrates that SERPINB7 maintains skin barrier through protein O-GalNAc glycosylation. These findings not only deepen our understanding of skin barrier biology but also provide new insights for developing therapeutic strategies for skin barrier-related diseases.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal type of cancer with poor diagnosis and prognosis, and overcoming gemcitabine-resistant (Gem-R) is a major obstacle in its treatment. Given the important role of glutamine (Glu) metabolism in tumor drug resistance, we investigated the role and exact mechanism of transglutaminase type 2 (TGM2) in influencing PDAC sensitivity to gemcitabine. In this study, we found that TGM2 exhibited elevated expression levels in Gem-R cells and tissue samples from patients with clinically resistant PDAC. Mechanistically, downregulation of TGM2 suppressed the proliferation of Gem-R PDAC cells both in vitro and in vivo by modulating Glu metabolism. RNA sequencing analysis revealed that the mechanism by which targeting TGM2 inhibits drug resistance in Gem-R PDAC cells may be associated with purinergic receptor P2X7 (P2RX7) within the GO:0014049 pathway (positive regulation of glutamate secretion). P2RX7 is highly expressed in Gem-R PDAC cells and tissue samples, and it participates in Glu metabolism and mitophagy in Gem-R PDAC cells. Furthermore, Glu has also been found to induce mitophagy. Lastly, TGM2 and P2RX7 form a positive feedback regulatory loop, jointly regulating Glu metabolism and mitophagy, thereby promoting drug resistance in Gem-R PDAC cells. These data suggest that the TGM2-P2RX7 loop promotes Gem-R in PDAC by improving Glu metabolism and mitophagy, highlighting its potential as a crucial therapeutic target for PDAC.

Deubiquitinating enzymes (DUBs) are critical regulators of protein turnover and have emerged as key players in cancer progression. In this study, we demonstrated that ubiquitin C-terminal hydrolase L1 (UCHL1) is upregulated in non-small cell lung cancer (NSCLC) and drives tumor metastatic progression, and we identified Twist1, a transcription factor that governs epithelial-mesenchymal transition (EMT), as a downstream target of UCHL1. Depletion of UCHL1 attenuated Twist1-mediated metastatic capacity in NSCLC cells both in vitro and in vivo. Mechanistically, UCHL1 directly interacts with Twist1 and stabilizes Twist1 protein levels through the enzymatic cleavage of K11- and K63-linked ubiquitin chains. Clinically, immunohistochemistry of human NSCLC tissues revealed a positive correlation between UCHL1/Twist1 expression and metastatic progression, with elevated levels of both proteins predicting poor prognosis. Our findings reveal a critical pathway through which UCHL1-mediated deubiquitination sustains Twist1 stability, revealing a novel posttranslational regulatory axis involved in cancer metastasis and progression and highlighting promising therapeutic targets for metastatic NSCLC.

Malignant tumors, as one of the leading causes of mortality, pose great threats to global public health. Serine/Arginine-rich Splicing Factor 7 (SRSF7), a core splicing regulatory protein of the SRSF family, plays a crucial role in maintaining RNA stability, facilitating alternative splicing, and assisting RNA nuclear export. It also exhibits significantly aberrant expression among various cancers, including lung, colorectal, liver, and oral cancer. This review examines the molecular mechanisms of SRSF7 in tumorigenesis, with a focus on its role in the epigenetic reprogramming of related tumors. Specifically, it explores the abnormal regulation of the cell cycle, the regulation of non-coding RNA, the control of RNA methylation, and the reprogramming of glucose metabolism. Additionally, this review examines the role of SRSF7 in the tumor immune microenvironment through alternative splicing and immune evasion through the immune checkpoint PD-1. It also highlights the role of SRSF family members in tumor resistance, illustrating how alternative splicing contributes to tumor chemoresistance. Although SRSF7 shows significant promise in tumor intervention therapies, more experimental and clinical studies are still needed to evaluate its clinical application. This review enhances our understanding of the molecular landscape of SRSF7 in tumorigenesis with great potential to become a key node in tumor-targeted therapy and companion diagnostics, driving translational potential from mechanisms to clinical applications.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Its incidence is increasing and is closely related to advanced liver disease. Interactions in the HCC microenvironment between tumor cells and the associated stroma actively regulate tumor initiation, progression, metastasis, and therapy response. Effective drug development increasingly requires advanced models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screen on an advanced HCC patient-derived chip (PDChip) model. The vascularized HCC PDChip models include relevant cellular players of the HCC microenvironment. We assessed the effect of 28 treatment conditions on a panel of 8 primary HCC tumors and 2 cell lines. Approximately 1200 HCC PDchips were grown under perfusion flow, exposed to treatments, and subsequently assessed for viability, tumor-associated vasculature responses and chemokine and cytokine changes. Although the SoC therapeutics sorafenib and lenvatinib reduced culture viability and produced profound changes in the organization of the vascular beds, they did not affect the tumor cell population in these cultures. Atorvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, reduced PDChips viability but did not affect vascular bed organization. Sorafenib, lenvatinib and atorvastatin also affected chemokine and cytokine release. Tocilizumab, galunisertib, and vactosertib decreased the level of IL6, a relevant prognostic marker for HCC, while IL6 was increased by halofuginone. In conclusion, HCC PDChip models enabled a detailed evaluation of drug-induced responses in the tumor and associated microenvironment, highlighting their importance in preclinical research for understanding diseases and developing new drugs.

Renal fibrosis is a major driver of chronic kidney disease (CKD) progression, yet targeted therapies remain limited due to incomplete understanding of key molecular mechanisms. While IL-1-mediated inflammation and mitochondrial dysfunction are recognized contributors, the precise links between IL-1 signaling, fibrosis, and mitochondrial homeostasis are unclear. Here, we investigated the therapeutic effects of recombinant human IL-1 receptor antagonist (rhIL-1Ra) in both acute (UUO) and chronic (5/6Nx) mouse models of kidney injury, as well as in vitro TGF-β1-stimulated kidney cells. rhIL-1Ra significantly attenuated renal fibrosis, inflammation, and functional impairment in vivo. Mechanistically, rhIL-1Ra suppressed TGF-β1-induced expression of the E3 ubiquitin ligase RNF182, which we show mediates MFN2 ubiquitination and degradation, leading to mitochondrial dysfunction. Inhibition of RNF182 by rhIL-1Ra stabilized MFN2, preserved mitochondrial respiration and ATP production, and reduced oxidative stress. Rescue experiments confirmed the centrality of the RNF182-MFN2 axis in fibrotic and mitochondrial injury. Our findings reveal a novel IL-1R/RNF182/MFN2 pathway linking inflammation to mitochondrial and fibrotic pathology, supporting RNF182 as a promising target and rhIL-1Ra as a potential therapy for CKD.

Thin endometrium (TE, ≤7 mm) is widely recognized as a critical cause of infertility, recurrent pregnancy losses, and placental abnormalities. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a crucial role in tissue repair, but its effect on endometrial regeneration has been less investigated. We employed a thin endometrium mouse model established through unilateral 95% ethanol injury in an animal study and thin endometrium patients in a parallel clinical study. Both mice and patients were randomly apportioned into two groups: the Saline group and the GM-CSF group. We demonstrate that GM-CSF significantly increases endometrium thickness and gland number, promotes the proliferation of stromal cells, and improves the number of embryo implantation sites in the mouse model (P < 0.05). GM-CSF significantly (P < 0.05) promotes the proliferation of glandular cells, but not stromal cells in humans due to species-specific differential effects. GM-CSF treatment in humans induces upregulation of tissue repair/regeneration genes and enrichment of angiogenesis, cell adhesion, and epithelial proliferation pathways at the transcriptional level. The pregnancy outcomes, implantation rate (24.10% vs. 17.39%), and clinical pregnancy rate (34.78% vs. 26.32%), were both enhanced by GM-CSF compared to the Saline group. The delivery rate shows no statistically significant discrepancy between the two groups. GM-CSF has a positive role in endometrial regeneration and pregnancy outcomes in a thin endometrium. In conclusion, our study provides a novel therapeutic approach for thin endometrium and related infertility.

Osteoporosis, characterized by diminished bone density and compromised microstructure, presents a significant healthcare challenge, particularly in the aging population. The primary approach in addressing osteoporosis involves the use of anti-resorptive agents as well as medications that promote bone formation. However, these therapies have limitations, prompting the exploration of novel therapeutic targets. Prolyl Endopeptidase (PREP), an endopeptidase with diverse roles in neuronal peptide metabolism and various physiological processes, has emerged as a potential player in osteoporosis, though its mechanistic involvement remains largely uncharted. This study delves into the role of PREP in osteoporosis, aiming to unravel its underlying mechanisms and therapeutic potential. Utilizing murine models and cellular experiments, we systematically investigate how PREP influences osteoblast differentiation and osteoporosis pathogenesis. Our results suggest activation of the Wnt pathway counteracts the inhibitory effects of PREP deletion on osteoblast differentiation. Additionally, we observe that PREP affects osteoclastogenesis, influencing osteoclast differentiation and bone resorption capacity. Moreover, our investigation extends to age-related osteoporosis, demonstrating PREP's potential therapeutic efficacy beyond estrogen-deficiency-induced osteoporosis. In summary, this study advances our understanding of PREP's multifaceted role in osteoporosis pathogenesis. It underscores PREP as a potential therapeutic target for osteoporosis, offering fresh perspectives on its etiology and treatment.

The common fungal pathogen, Candida albicans, relies on the pore-forming toxin candidalysin to damage host cells. Cells counteract pore-forming toxins by Ca²⁺-dependent mechanisms, such as microvesicle shedding and annexin recruitment to resist cholesterol-dependent cytolysins like streptolysin O (SLO), or annexin involvement and patch repair in the case of aerolysin. However, the specific Ca²⁺-dependent repair pathways engaged in response to candidalysin remain poorly understood. Here, we determined the involvement of different Ca²⁺-dependent repair mechanisms to candidalysin and compared responses to SLO and aerolysin using flow cytometry and high-resolution microscopy. We report that candidalysin triggered Ca²⁺-dependent repair, but patch repair and ceramide failed to provide significant protection. MEK-dependent repair and annexins A1, A2 and A6 contributed partially to repairing damage caused by candidalysin. However, annexin translocation after candidalysin challenge was delayed compared to SLO or aerolysin challenge. Surprisingly, extracellular Cl^- improved cell survival after candidalysin challenge, but not after challenge with SLO or aerolysin. Finally, we found that candidalysin is removed via extracellular vesicle shedding. These findings reveal that Ca²⁺-dependent microvesicle shedding protects cells from candidalysin and can be engaged by multiple molecular mechanisms during membrane repair.

Clinical variability in COVID-19 is partly explained by host genetic factors, including inborn errors of immunity. We investigated a patient with a heterozygous nonsense mutation in the TLR3 gene (p.Trp769*) by generating human-induced pluripotent stem cells (hiPSCs) and differentiating them into lung organoids (hLORGs). TLR3-mutated hLORGs showed reduced basal expression of TLR3 and downstream signaling genes. Following infection with a pseudotyped SARS-CoV-2 virus and live SARS-CoV-2, RNA-Seq and qPCR analyses revealed significant upregulation of fibrinogen genes (FGA, FGG), which are associated with severe COVID-19. Interestingly, TLR3 expression remained inducible upon infection, despite the loss-of-function mutation. Our patient-derived hLORG model recapitulates the pathophysiological features of the patient and provides a platform to investigate host-virus interactions and test targeted therapies for genetically at-risk individuals.