Cell Death & Disease最新文献

Ferroptosis, an iron-dependent form of programmed cell death driven by toxic lipid peroxide accumulation, plays a critical role in various diseases, making its modulation a promising therapeutic strategy. In this study, we identified defactinib, a specific inhibitor of FAK as a novel ferroptosis suppressors. We demonstrate that FAK/SRC-JNK signaling positively regulates ferroptosis by upregulating ACSL4, a critical mediator of ferroptosis. We reveal that a subset of JNK downstream transcription factors, including ATF2, NFATC1, NFATC3, and SMAD4, promote ferroptosis through direct binding to the ACSL4 promoter and activation of its expression. In contrast, another subset of JNK-associated transcription factors, including c-Jun, STAT3, ELK1, and HSF1, inhibit ferroptosis by binding to the ACSL4 promoter and repressing its expression. The net effect of FAK/SRC-JNK signaling in our models is a significant upregulation of ACSL4 and promotion of ferroptosis. Notably, elevated FAK/SRC-JNK signaling sensitizes cancer cells to ferroptosis-inducing therapies, while inhibition of the FAK/SRC-JNK signaling pathway protects against acute pancreatitis by suppressing ferroptosis. These findings highlight the central role of FAK/ SRC-JNK signaling in controlling ferroptotic cell death and underscore the therapeutic potential of targeting FAK/ SRC-JNK mediated ferroptosis, offering new avenues for the treatment of cancer and acute pancreatitis.

Pancreatic ductal adenocarcinoma (PDAC) is a notoriously lethal malignancy with high epithelial-mesenchymal transition (EMT) baseline. EMT is associated with enhanced cell plasticity and contributes to tumor adaption and evolution. EMT programs fuel PDAC invasion, metastasis, and treatment resistance, but directly targeting EMT has yielded limited clinical benefits. Transdifferentiation therapy that exploits cell plasticity and redirects malignant cell fate offers an orthogonal approach beyond pathway inhibition. To validate the feasibility of transdifferentiation in epithelial malignancies such as PDAC, we applied an adipogenesis protocol in seven human PDAC cell lines and distinguished AsPC-1 with intensified adipocyte features (intracellular lipid droplets accumulation, elevated adiponectin, CEBPA, PPARG, FABP4 expression). AsPC-1 was converted into adipocyte-like, post-mitotic cells with lipometabolic (enhanced adiponectin secretion and lipolysis) and phenotypic reprogramming (proliferation inhibition, G1 cell cycle arrest, and EMT key transcription factors downregulation). Multi-omics showed global chromatin compaction and transcriptome-wide repression of EMT and metastatic programs in induced AsPC-1 cells, with suppressed MMPs and TGF-β, indicating diminished metastatic potential. Therefore, we further evaluated the possibility of clinical translation by murine orthotopic and hepatic metastasis models, finding adipogenesis induction reduced primary tumor burden and slowed metastatic progression. The adipocyte-like phenotype in vivo was sustained through one-month observation period following induction drug withdrawal. This study establishes a plasticity-oriented "convert-instead-of-kill" strategy for EMT-high PDAC, suggesting a potential for future studies to investigate rational combinations (e.g., transdifferentiation therapy combined with targeted or immunotherapy) to exploit lineage conversion.

In clinical practice, triple-negative breast cancer (TNBC) patients with varying levels of lipid metabolism exhibit differences in tumor shear-wave elastography (SWE) stiffness and prognosis, but this association with unclear mechanism. In this study, a clinical cohort from FUSCC (n = 147) demonstrated that both elevated BMI and higher SWE stiffness were significantly associated with poorer long-term prognosis in TNBC patients, and these associations were further validated in multi-TNBC animal models. Our findings emphasize the role of SWE stiffness in capturing BMI-related alterations in the tumor mechanical microenvironment. Based on integrated lipidomic and transcriptomic analyses, we demonstrated that diacylglycerol (DAG) serves as a critical lipid molecule promoting elevated SWE stiffness and malignant progression. Mechanistically, DAG upregulates TGF-β1 expression through PKC-mediated enhancement of CREB1 phosphorylation in multiple TNBC cell lines, directly promoting TNBC progression and activating cancer-associated fibroblasts. This creates a self-sustaining feedback loop that accelerates malignancy. Finally, we confirmed that the DAG/PKC/CREB1/TGF-β1 signaling axis profoundly regulates SWE imaging stiffness in TNBC models, with further validation in clinical samples. Our study establishes SWE stiffness as a non-invasive imaging biomarker for the activation of this specific pro-metastatic pathway, providing a mechanistic basis for interpreting SWE features through a biological lens and paving the way for its application in prognosis prediction and tailored therapeutic strategies for high-risk TNBC patients.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck. Early-stage OSCC is primarily treated using surgery; advanced-stage OSCC is managed using a multidisciplinary approach, including surgery combined with adjuvant radiotherapy and chemotherapy. However, tumor recurrence and metastasis remain major challenges, with a 5-year survival rate of ~50%. Dysregulation of transcription factors is associated with the pathogenesis of various cancers. This study focused on the role of ZIC2, a member of the zinc finger protein family, in OSCC. ZIC2 was identified as a prognostically relevant transcription factor in OSCC through bioinformatic analysis, showing high expression in OSCC and association with poor prognosis in patients. In vitro and in vivo, ZIC2 knockdown inhibited the proliferation, migration, invasion, and spheroid formation ability of OSCC cells and restored their sensitivity to chemotherapeutic drugs; overexpression of ZIC2 showed the opposite effect. RNA-seq and targeted metabolomics analyses revealed that in OSCC cells with zic2 knockdown, the expression of glycerophosphocholine (GPC) and the key rate-limiting enzyme LYPLA2 was decreased. LYPLA2 overexpression rescued the effects of ZIC2 knockdown on the proliferation, migration, and invasion of OSCC cells. GPC increased the stemness of OSCC tumor cells; ZIC2-regulated GPC metabolism through LYPLA2, inducing changes in the expression of the cancer stem cell markers Nanog and OCT4. In conclusion, we identified ZIC2 as an OSCC stemness-related gene, a potential therapeutic target for OSCC, providing new insights for treating OSCC.

The resistance to radiotherapy of prostate cancer is driven by interactions within the tumor microenvironment, particularly between prostate cancer cells and tumor-associated macrophages, however the underlying mechanisms remain poorly understood. In this study, we found that STAT1 enhanced the transcription of critical glycolytic enzymes, leading to an increase in lactate secretion from prostate cancer cells. Then, the lactate was transported to macrophages via the MCT1 transporter, activating the NFκB1 pathway, which subsequently promoted macrophage polarization to the M2 phenotype and activated the transcription of MCP-1. MCP-1 was secreted from macrophages interacted with the CCR2 receptor on prostate cancer cells, thereby activating the JAK/STAT1 pathway, ultimately contributing to the progression of prostate cancer and its resistance to radiotherapy. Taken together, our findings identified a STAT1/lactate/NFκB1/MCP-1 positive feedback mechanism as a driver of prostate cancer progression and resistance to radiotherapy that functioned by interaction to macrophages, which could be potential therapeutic targets for the advanced prostate cancer.

The lysosomal regulator complex member LAMTOR1 serves as a crucial pivot that recruits the mechanistic target of rapamycin complex 1 (mTORC1) to the lysosomal surface, thereby influencing biological processes such as cell growth and cancer progression. In renal cell carcinoma (RCC), existing studies reveal that mTORC1 signaling contributes to cancer progression. However, the precise regulatory mechanisms underlying mTOR signaling in RCC remain unclear and warrant further investigation. Here, we demonstrate that the palmitoylation enzyme Zinc Finger DHHC-Type Containing 9 (ZDHHC9) activates the mTOR signaling pathway, thereby accelerating cancer progression and highlighting its potential role in RCC. In our study, we identified that ZDHHC9 specifically palmitoylates LAMTOR1 at its Cys3/4 residues, enhancing the recruitment of mTORC1 and subsequently activating the mTOR signaling cascade. Collectively, our findings provide novel insights into the pathogenesis of RCC and establish ZDHHC9 as a key mediator of RCC progression through the palmitoylation of LAMTOR1, which may serve as a promising target for the diagnosis and treatment of this malignancy.

Colorectal cancer (CRC) is the third most common malignant tumor worldwide, with high recurrence and metastasis rates significantly impacting outcomes. This study explores the role of FBXO6, a ubiquitination-related protein, in regulating CRC malignancy, particularly cell migration and invasion. Our analysis reveals that higher FBXO6 expression correlates with better prognosis in CRC patients, although its expression decreases in advanced-stage tumors. Functional studies demonstrate that FBXO6 overexpression suppresses the invasive and migratory abilities of HCT116 and RKO cells and reduces single-cell colony formation. In contrast, FBXO6 knockdown promotes these malignant traits. Immunoprecipitation and mass spectrometry analyses identified ITGB1 as a key substrate of FBXO6, with potential prognostic relevance in CRC. Subsequent in vitro assays confirmed this interaction, revealing that FBXO6 binds ITGB1 at its glycoprotein recognition site, thereby reducing ITGB1 stability and attenuating downstream FAK/PI3K/AKT/ERK signaling. ITGB1 overexpression counteracts the suppressive effects of FBXO6, restoring downstream signaling activity. In vivo xenograft models further validate these findings: FBXO6 overexpression reduces tumor growth, Ki67 levels, and ITGB1-associated signaling. Additional rescue experiments show that FBXO6 counteracts the tumor-promoting effects of ITGB1 overexpression. In conclusion, FBXO6 suppresses CRC cell proliferation, migration, and invasion by targeting ITGB1 for ubiquitination and disrupting key oncogenic signaling pathways, thereby supporting its potential as a prognostic biomarker and candidate therapeutic target in CRC.

Metabolic reprogramming has garnered significant attention in recent years due to its therapeutic potential in cancer treatment. However, identifying responsive tumor subpopulations remains a major obstacle in developing metabolism-targeted therapies, as metabolic vulnerabilities vary among cancers with different oncogene expression profiles. Therefore, elucidating the association between oncogene expression and metabolic characteristics could enable more precise metabolic interventions in clinical settings. Using pharmacological approaches, we demonstrate that VRK2-deficient pancreatic cancer (PC) cells exhibit heightened vulnerability to glutathione (GSH) metabolic pathway inhibition. This susceptibility stems from reduced basal GSH levels caused by impaired plasma membrane expression of SLC7A11. Mechanistically, we reveal that VRK2 inhibition disrupts endoplasmic reticulum (ER)-to-Golgi trafficking of SLC7A11, consequently diminishing GSH biosynthesis and predisposing PC cells to ferroptosis. Collectively, our findings establish a novel link between the oncogene VRK2 and GSH synthesis metabolism, providing a molecular basis for developing stratified metabolic therapies for PC patients.

Metabolic reprogramming and epigenetic alterations promote oral squamous cell carcinoma (OSCC). Lactate-dependent histone modification is a novel histone mark that connects the epigenetic process of lactylation to glycolytic metabolites. However, the role of histone lactylation in oral carcinogenesis remains poorly understood. In this study, the levels of histone lactylation in oral leukoplakia (OLK) and OSCC tissues were determined by immunohistochemistry. The involvement of histone lactylation in OSCC initiation was assessed by the inhibition of lactylation using glycolysis inhibitors or silencing lactate dehydrogenase A (LDHA), both in vitro and in vivo. CUT&Tag, scRNA-seq, ChIP-qPCR, and rescue experiments were conducted to explore the potential molecular mechanism of H3K18 lactylation (H3K18la) in OSCC tumorigenesis. Histone lactylation, particularly H3K18la levels were elevated in OLK and OSCC tissues. The inhibition of histone lactylation repressed the malignant phenotypes of OLK and OSCC cells in vitro. Glycolysis inhibitors blocked the formation of precancerous lesions and OSCC in the 4NQO-induced tongue carcinogenesis model. Mechanistically, H3K18la activated the transcription of thymidine kinase 1 (TK1) and increased TK1-mediated pyrimidine biosynthesis, resulting in oral carcinogenesis. TK1 downregulation inhibited the Wnt signaling pathway via RhoA. Moreover, the Wnt/β-catenin inhibitor XAV939 reduced lactate production and H3K18la levels. Here, we demonstrate that the glycolysis/H3K18la/TK1/β-catenin positive feedback loop exacerbates dysfunction in OSCC initiation. These findings reveal a novel link between epigenetic regulation and lactate-driven metabolic reprogramming, which may lead to the development of innovative lactylation treatment approaches for OSCC therapy.

Colorectal cancer is initiated by loss of APC, which drives expansion of LGR5+ intestinal stem cell (ISC) populations. Whilst LGR5 + ISC expansion is a critical step for tumour initiation and progression, its regulation is poorly understood. Emerging evidence suggests post-transcriptional RNA modifications play a key role in cancer biology, but their role in CRC initiation has not been explored. Here, we identify the m⁵C methyltransferase NSUN2 as a key regulator of ISC expansion and intestinal tumourigenesis. NSUN2 is upregulated in multiple CRC mouse models and human tumours, and its depletion impairs ISC expansion and hyperproliferation, leading to reduced tumour initiation. Transcriptome-wide bisulfite sequencing revealed that NSUN2 mediates m⁵C methylation on mRNAs encoding key ISC regulators and components of the MAPK/ERK pathway. Mechanistically, loss of NSUN2 reduces ERK phosphorylation in Apc-deficient models, and oncogenic Kras^G12D expression is sufficient to restore ERK signalling and rescue ISC expansion. Together, this establishes a novel role for NSUN2 as a key regulator of ISC-driven CRC initiation and describes a critical molecular mechanism linking m⁵C methylation to MAPK-driven stem cell transformation.