Cell Death & Disease最新文献

Pulmonary fibrosis (PF) is a chronic progressive lung disorder characterized by overactivation of Wnt/β-catenin signaling and limited therapeutic efficacy. This study identifies sorting nexin 3 (SNX3), a retromer-associated protein, as a dual regulator of PF pathogenesis through coordinated molecular mechanisms. SNX3 is significantly upregulated in PF patients' lungs and bleomycin-induced murine fibrotic models, with predominant localization in alveolar type 2 (AT2) epithelial cells correlating with β-catenin hyperactivation and fibrotic progression. Genetic ablation of SNX3 in AT2 cells attenuated Wnt/β-catenin signaling, collagen deposition, and pulmonary dysfunction, while SNX3 overexpression exacerbated these phenotypes. Mechanistic studies further elucidated two distinct SNX3-driven regulatory pathways. Wls is rescued by SNX3 from lysosomal degradation to sustain Wnt ligand secretion and canonical pathway activation. In addition to Wls, casein kinase 1α (CK-1α) is identified as a novel cargo protein for SNX3, which mediates its plasma membrane recruitment via Rab5a-dependent endosomal recycling, bypassing the β-catenin destruction complex, ultimately suppressing proteasomal degradation of β-catenin. This dual regulatory mechanism positions SNX3 as a master coordinator of both Wnt-dependent and -independent β-catenin signaling in PF. Furthermore, we screened inhibitors targeting SNX3 and identified a novel small molecule, LC4, which effectively ameliorated pulmonary dysfunction and reversed pulmonary fibrosis. Tetrahedral framework nucleic acids (TDNs), known for their excellent biocompatibility and drug delivery capacity, were utilized to develop a multifunctional nanodrug delivery system (TDN-LC4) to enhance the treatment of PF. By optimizing this loading approach, we improved LC4 delivery efficiency, enhanced its therapeutic potential, and minimized off-target effects. Our findings reveal SNX3 as a master coordinator of dual Wnt-dependent and -independent β-catenin activation, and propose TDN-LC4 as a potential therapeutic strategy to disrupt pathogenic signaling redundancy in PF pathogenesis.

Neddylation, a protein post-translational modification, regulates diverse molecular biological processes in tumors, governing protein stability, function, subcellular localization, and transcriptional activity. Thus, it plays an essential role in sustaining tumorigenicity and the hallmarks of cancer. In tumors, neddylation is triggered by various forms of cellular stress, involving hypoxia, oxidative stress, and tumor metabolites, all of which drive tumor initiation and progression. This review explores the critical regulatory mechanisms and pathological features of the neddylation cascade in terms of tumor malignant evolution and therapeutic resistance. Additionally, it examines therapeutic strategies targeting NEDD8 modification, offering novel avenues for innovative cancer treatments by disrupting this dynamic, reversible modification process.

There is compelling evidence that TNF preferentially activates and expands CD4⁺Foxp3⁺ regulatory T cells (Tregs) through TNFR2. However, the precise mechanisms underlying TNF-TNFR2 pathway-mediated Treg proliferation remain to be fully elucidated. In this study, using RNA-seq profiling of TNFR2⁺ and TNFR2-deficient Treg cells, we identified that Trip13 is required for promoting TNF-TNFR2 pathway-mediated Treg expansion. Mechanistically, TRIP13 inhibited UBE4A-mediated ubiquitination degradation of HAT1 by directly binding to HAT1, thereby competing with UBE4A and promoting Treg expansion. In addition, TRIP13's ATPase activity was essential for its binding to HAT1, which promoted Treg expansion by increasing Foxp3 expression. In a mouse colitis model, TRIP13 overexpression markedly alleviated colon inflammation by enhancing Treg expansion, an effect that was reversed by HAT1 knockdown. Conversely, genetic ablation of TRIP13 substantially reversed the effects induced by HAT1 overexpression, including enhanced Treg expansion and attenuation of colitis. These findings illustrate the TRIP13/HAT1 axis-mediated mechanism for TNF-TNFR2-induced Treg expansion and indicate that targeting TRIP13 may offer therapeutic potential for autoimmune and inflammatory diseases.

All cancers arise from the malignant transformation of normal cells, yet their cells-of-origin remain challenging to identify due to the inability to directly observe dynamic changes in human tumors. Retinoblastoma (Rb), a malignant intraocular cancer, serves as a well-established model for investigating the molecular and cellular mechanisms underlying tumorigenesis. While the maturing cone precursors (CPs) have been proposed as the cellular origin of human Rb, it is unclear whether other retinal cell types are similarly sensitive to RB1 inactivation. In this study, we developed RB1-deficient human retinal organoids (ROs) models using RB1^-/- or RB1^+/- human induced pluripotent stem cells (hiPSCs). RB1^-/- hiPSCs generated tumor cells that recapitulated key features of human Rb and formed serial orthotopic xenografts. Importantly, RB1 loss induced overproliferation of ATOH7⁺ neurogenic retinal progenitor cells (nRPCs), which disrupted retinal development by generating ectopic dividing early-born retinal cells (retinal ganglion cells and CPs). Single-cell RNA sequencing analysis confirmed that ATOH7⁺/RXRγ⁺ nascent CPs survived and ultimately drove Rb tumorigenesis. In contrast, monoallelic RB1 inactivation resulting in low pRB expression did not induce proliferation of nascent CPs, but only triggered overproliferation of nRPCs, leading to a retinocytoma-like phenotype. Finally, a potential therapeutic target for Rb was identified from multi-omics data and validated through knockdown experiment and a small-molecule inhibitor. Our findings demonstrate, for the first time, that nRPCs are the most sensitive cells to RB1 loss inducing abnormal proliferation of nascent retinal cells, while ATOH7⁺ nascent CPs represent the earliest cellular origin of human Rb. These insights may facilitate the development of targeted therapies for Rb.

Endogenous nitric oxide (NO) produced by nitric oxide synthases (NOSs) plays an important immunosuppressive role in the tumor microenvironment. In melanoma, NOS1 expression increases with tumor progression and correlates with tumor immune escape through the inhibition of type I interferon (IFN) signaling. However, the immune regulatory role and related mechanisms of NOS1, as well as its impacts on immune therapies such as immune checkpoint blockade (ICB) in melanoma, remain unclear. Here, we found that NOS1 expression induces IRF7 modification by S-nitrosylation at the C435 site in mice (C481 in humans), which functionally promoted tumor growth in mouse models. Mechanistically, IRF7-C435-SNO inhibited IFNβ transcription under PRR signal activation, leading to a disorder in the initiation of the type I interferon response in melanoma cells. In a melanoma mouse model, IRF7-C435-SNO decreased the infiltration and activation of CD8 + T cells in the tumor microenvironment by reducing antigen presentation processes in tumor cells and inhibiting the maturation of DC1. Clinically, high expression of NOS1 correlated with poor survival prognosis and resistance to ICB anti-tumor therapies in melanoma cases with less immune cell infiltration. Our study suggests that NOS1 expression in melanoma characterizes IFN-I signal disorders in response to innate immune stimulation through IRF7 s-nitrosylation. Targeting NOS1 signaling might be beneficial for overcoming immune therapeutically resistance, particularly in immune-cold melanoma phenotype.

Immunotherapy has emerged as a promising approach in the management of cancer. However, the suboptimal efficacy of immunotherapy monotherapy underscores the need to develop more effective combination strategies. In this study, we focused on PSMD1 to investigate its role and the molecular pathways by which it regulates the response to immunotherapy in hepatocellular carcinoma (HCC). In HCC, elevated PSMD1 levels are linked to associated with poor prognosis. PSMD1 was predominantly expressed in malignant epithelial cells. Tissue microarray results showed that PSMD1 was highly expressed in tumor tissues. Silencing PSMD1 suppressed HCC cell proliferation and promoted apoptosis in both in vitro and in vivo models. Additionally, PSMD1 suppression decreased PD-L1 expression, thereby enhancing the therapeutic efficacy of anti-PD-1 therapy. Mechanistically, publicly available single-cell RNA sequencing (scRNA-seq) datasets indicated that PSMD1 positively regulates β-catenin signaling. Silencing of PSMD1 decreased the expression of β-catenin pathway-associated proteins. Further analysis via mass spectrometry revealed that PSMD1 interacts with Rhotekin (RTKN) and suppresses its ubiquitination. Subsequent experiments revealed that RTKN enhances β-catenin expression through AKT phosphorylation, thereby increasing PD-L1 transcription. In summary, our findings demonstrate that PSMD1 regulates RTKN protein expression, whereas RTKN facilitates β-catenin expression via AKT phosphorylation. This mechanism contributes to HCC progression and the effectiveness of immunotherapy. The PSMD1/RTKN/β-catenin axis could serve as a promising therapeutic target for HCC.