Cell Death & Disease最新文献

Immune checkpoint inhibitors (ICIs) are widely used in clinical oncology owing to their effectiveness against various tumors. However, by enhancing their immune responses, these inhibitors can trigger immune-related adverse events (irAEs) affecting various organ systems. Notably, pulmonary complications, particularly immune checkpoint inhibitor-related pneumonitis (ICIP), have emerged as one of the leading causes of treatment-related mortality in patients receiving ICIs. Given the limitations of current ICIP treatments, mesenchymal stem cells (MSCs) represent a promising therapeutic strategy owing to their immunomodulatory properties and ability to promote tissue repair. This article reviews recent advances in ICIP and proposes the potential applications of MSC therapy, emphasizing the need for further research into its efficacy and safety to improve ICIP management.

Replication protein A (RPA) plays a vital role in replication stress response, with RPA-coated single-stranded DNA (ssDNA) acting as a critical platform for the coordination of the genome surveillance machinery. In previous studies, we reported that the lamin-associated protein LAP2α interacts physically with RPA, aiding its localization to damaged chromatin for genome protection. However, the significance of the LAP2α-mediated RPA deposition in tumor progression remains unclear. Here, we reveal that LAP2α promotes breast tumorigenesis by counteracting replication stress-induced DNA damage. Furthermore, we demonstrate that defects in RPA loading caused by LAP2α deficiency slow breast tumor growth and sensitize tumors to chemotherapeutic treatments. In addition, we found that LAP2α could directly stimulate the loading of RPA onto ssDNA. Collectively, our study characterizes a critical role of LAP2α-enhanced RPA loading in promoting breast tumorigenesis and positions the LAP2α-RPA complex as a promising target for therapeutic intervention in breast cancer.

Recurrence and metastasis are the main causes of death in ovarian cancer (OC). Long non-coding RNAs (lncRNAs) are considered as good prognostic models and potential therapeutic targets for cancer patients because of their easy detection and strong correlation. Our study identifies an OC-associated lncRNA with tumor progression and therapeutic implications. It's found that lncRNA AC093895.1 is highly expressed in OC tissues and correlated with poor prognosis. AC093895.1 has a potentiating effect during the progression and metastasis of ovarian cancer. The effects of AC093895.1 on ovarian cancer cells are miR-1253 dependent. Results showed that by interacting with tumor-suppressive gene miR-1253 as competing endogenous RNA (ceRNAs), AC093895.1 significantly upregulated the downstream gene SOX4 of AC093895.1/ miR-1253 axis, leading to tumor metastasis. In addition, chromatin immunoprecipitation (ChIP) results further confirmed that SOX4 could bind to the AC093895.1 promoter, forming a positive feedback loop SOX4/AC093895.1/miR-1253/SOX4. Therapeutic strategy to break the loop through AC093895.1 knockdown exhibited attenuated OC growth and metastasis in vivo both in SK-OV-3 subcutaneous model and pulmonary metastatic model. Our study unveiled the potentiating effects of SOX4/AC093895.1/miR-1253/SOX4 on ovarian cancer cell survival, migration, and invasion. AC093895.1 may be a promising patient prognostic biomarker and therapeutic candidate.Created with BioRender.com.

The liver contains both diploid and polyploid hepatocytes, but their functional differences remain poorly understood. Emerging evidence suggests that each ploidy state contributes to regeneration in an injury-specific manner. We hypothesized that diploid hepatocytes promote healing after acetaminophen (APAP)-induced liver injury. To study ploidy populations in vivo, we utilized mice with a lifelong liver-specific knockout of E2f7/E2f8 (LKO), which are enriched in diploid hepatocytes (> 70%) but otherwise normal. Control and LKO mice were treated with APAP (300 or 600 mg/kg), and injury was assessed over 0-96 h. Although both groups sustained injury, LKO mice showed improved survival, lower serum liver enzyme levels, and reduced necrosis and DNA fragmentation, indicating resistance to APAP-induced injury. To determine if resistance was due to E2f7/E2f8 loss or increased diploidy, we deleted E2f7/E2f8 in adult hepatocytes (HKO), a model that does not alter ploidy. Injury was similar between controls and HKO, ruling out gene deletion as the protective factor. Transcriptomic and protein analyses revealed minimal baseline differences; however, following APAP treatment, LKO livers exhibited reduced JNK activation and less mitochondrial injury. Finally, APAP-treated wild-type hepatocytes exhibited a shift toward lower ploidy, supporting the idea that diploid cells are more resistant to injury. These findings highlight hepatocyte ploidy as a key determinant of injury response and suggest a protective role for diploid hepatocytes in promoting liver resilience and regeneration.

Mitochondria are essential for cellular homeostasis, supplying key metabolites and energy. While post-translational modifications regulate mitochondrial enzymes, their roles remain less explored compared to those in the nucleus and cytoplasm. Here, we demonstrate that reversible arginine methylation governs the activity of several mitochondrial enzymes, with a particular focus on isocitrate dehydrogenase 2 (IDH2). We identify coactivator-associated arginine methyltransferase 1 (CARM1) as a mitochondrial enzyme that asymmetrically dimethylates IDH2 at R188, leading to enzymatic inhibition while enhancing protein stability. This modification is dynamically reversed by the lysine demethylases KDM3A and KDM4A, which restore IDH2 activity. Notably, despite its reduced stability, demethylated IDH2 promotes α-ketoglutarate production, enhancing mitochondrial membrane potential and oxygen consumption. These findings highlight the critical role of reversible arginine methylation in fine-tuning mitochondrial enzyme function and maintaining mitochondrial homeostasis.

Fuchs endothelial corneal dystrophy (FECD) is an age-related disorder characterized by excessive extracellular matrix (ECM) deposition and loss of corneal endothelial cells (CEnCs), eventually leading to corneal blindness. Despite known environmental and genetic contributors, the roles of aging and hormonal influences, particularly in the predominantly female population, remain underexplored in FECD. This study investigates the impact of chronic exposure to combined ultra-violet (UV-A) light and the oxidized estrogen metabolite 4-hydroxyestradiol (4-OHE2) on healthy CEnCs, primarily focusing on the cellular senescence pathway implicated in FECD pathogenesis. Our results show that prolonged exposure triggers G0/G1 cell cycle arrest through the p16-pRB pathway, inducing a senescence-mediated pro-secretory phenotype. The senescent cells in G0/G1 phase concurrently upregulated the fibrotic and extracellular matrix (ECM) markers indicating a complex relationship between senescence with fibrosis and ECM deposition. Additionally, multiplex analysis to detect senescence-associated secretory phenotype (SASP) after chronic exposure revealed significant upregulation of pathogenic factors such as IL-8 and IL-17, which were attenuated by SB225002 (anti-CXCR2) and secukinumab (anti-IL-17A). Senolytic cocktail of Dasatinib and Quercetin treatment alleviated fibrosis by selectively eliminating senescent cells and improved the survival of healthy cells. This study introduces a novel in vitro model of FECD, revealing the crucial role of cell cycle modulation, senescence and interleukins in the disease advancement and pathogenesis. The findings suggest that targeting senescence and cytokine-driven inflammation could be a promising therapeutic strategy for mitigating FECD progression.

Elevated expression of transglutaminase 2 (TGase 2, EC 2.3.2.13, protein-glutamine γ-glutamyltransferase, gene name TGM2) is known as one of the most upregulated genes during epithelial-mesenchymal transition (EMT) in ovarian cancer. Despite initial complete responses to conventional chemotherapy, ovarian cancer often recurs with metastasis, presenting a significant clinical challenge. Drug-resistant ovarian cancer cells exhibit markedly higher levels of TGase 2 compared to normal ovarian epithelium, which is associated with EMT activation, enabling them to evade chemotherapy effects. Intracellular TGase 2 is recognized as a key factor in maintaining the mesenchymal phenotype. Therefore, while EMT expression can be effectively reversed by inhibiting TGase 2, the underlying mechanism of this effect remains unclear. We found that TGase 2 promotes EMT by directly binding to glycogen synthase kinase-3β (GSK3β), promoting the stabilization of β-catenin. Domain mapping revealed that the N-terminus of TGase 2 interacts with the mid-region of GSK3β, leading to the autophagic degradation of GSK3β. Pharmacological disruption of this N-terminal interaction by streptonigrin, in combination with standard chemotherapy, extended overall survival in a xenograft model of ovarian cancer. This study identified TGase 2 as a pivotal regulator of EMT-driven metastasis and drug resistance.

Ultraviolet B (UVB) is a well-recognized trigger of cutaneous lupus erythematosus (CLE), yet its molecular basis remains largely undefined. Here, using single-cell transcriptomics and a lupus-prone mouse model, we identify keratinocyte-derived macrophage migration inhibitory factor (MIF) as a key amplifier of cutaneous inflammation through a self-sustaining feedback loop. Single-cell RNA sequencing reveals elevated MIF expression specifically within pathogenic, interferon-high keratinocyte subclusters associated with CLE, which is further validated across major CLE subtypes in clinical skin samples. In vitro, UVB irradiation dose-dependently induces the release of MIF from keratinocytes, which in turn promotes inflammatory signaling and matrix remodeling in both keratinocytes and fibroblasts. Mechanistically, we demonstrate that UVB irradiation activates the ribotoxic stress response (RSR), leading to the p38-C/EBPβ-mediated transcriptional upregulation of NLRP3 and GSDMD cleavage in keratinocytes. The ensuing GSDMD-dependent pyroptosis facilitates the release of MIF, primarily through GSDMD pores rather than vesicular secretion, which in turn amplifies the p38-C/EBPβ signaling pathway. Therapeutic disruption of this loop either by gene silencing via AAVs or pharmacological inhibition via microneedles, markedly attenuates epidermal hyperplasia and cytokine imbalance in lupus-prone mice. These findings uncover a previously unrecognized MIF-p38-GSDMD inflammatory loop contributes to the UVB-induced cutaneous lupus, offering both mechanistic insights and translational opportunities for CLE.

Enolase 1 (ENO1) is a glycolytic enzyme involved in tumor progression that performs a variety of classical and nonclassical functions. However, the mechanism by which it promotes tumor progression is still not fully understood. Here, we revealed that TGFβ1/Smad3 signaling triggered the symmetric dimethylation of arginine (SDMA) on ENO1 by protein arginine methyltransferase 5 (PRMT5), leading to membranous ENO1 translocation. Surface ENO1 interacts with monocarboxylate transporter 4 (MCT4) for lactate secretion, which recruits M2 macrophages and promotes an immunosuppressive tumor microenvironment (TME). Targeting surface ENO1 with HuL001, a first-in-class humanized antibody, significantly reduced glycolysis, decreased extracellular lactate accumulation, reprogrammed macrophage polarization and inhibited tumor growth and distant metastasis. Moreover, targeting surface ENO1 significantly increased the therapeutic response to radiotherapy and delayed tumor regrowth by increasing antitumoral M1 macrophages and cytotoxic CD8⁺ T cells infiltration within TME. These results indicated that targeting surface ENO1 remodeled the tumor microenvironment and provided better therapeutic effects to radiotherapy in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC).