Cell Death Discovery最新文献

Cholestatic liver injury, characterized by direct exposure of hepatocytes to retained bile components with elevated concentrations, represents a common manifestation of various hepatobiliary disorders with persistent threats to long-term patient survival despite existing therapies. As the primary route for copper elimination, cholestasis raises questions about the role of copper in cholestatic liver injury and its specific molecular mechanisms. Our single-center retrospective study revealed elevated serum copper levels in subjects with increased gamma-glutamyl transferase compared to controls. Single-cell sequencing of biliary atresia (BA) patients' cholestatic liver specimens demonstrated downregulation of FDX1, a key cuproptosis marker, in BA hepatocytes. Bile duct-ligated rats under high-copper diets exhibited accelerated liver injury, attenuated by copper chelator tetrathiomolybdate (TTM). In vitro, copper chloride/elesclomol-induced DLAT monomer reduction and oligomerization alongside impaired lipoylation. Given the special coexistence of copper overload and accumulated bile components within the hepatic microenvironment, notably, we found that taurocholic acid potentiated hepatic copper accumulation under cholestatic conditions. Mechanistically, transcriptomic analysis implicated smoothened signaling inhibition in cuproptosis progression, with smoothened agonist (SAG) restoring DLAT expression and cellular viability. Interestingly, FDX1 overexpression enhanced cuproptosis resistance of hepatocytes through DLAT monomer stabilization and LIAS-mediated lipoylation. Cholestasis-induced copper overload drives liver injury via taurocholic acid-exacerbated and FDX1-mediated cuproptosis. Our findings propose TTM and SAG as therapeutic candidates and reveal complex FDX1 regulatory roles, suggesting novel approach for managing cholestatic liver injury.

Acetylation is an important post-translational modification (PTM) of proteins and plays critical roles in multiple biological processes. The modes of cell death represent different pathways leading to the final outcome of "death" for the cell, with apoptosis, ferroptosis, and pyroptosis being the most common forms of cell death. In recent years, research has found that acetylation modifications influence various biological processes, ultimately playing a role in the regulation of apoptosis, ferroptosis, and pyroptosis. This article introduces the molecular effects of acetylation and enzyme/non-enzyme regulation, systematically summarizing the regulatory mechanisms of apoptosis, ferroptosis, and pyroptosis. It ultimately focuses on the genes and proteins associated with the regulation of apoptosis, ferroptosis, and pyroptosis, providing a comprehensive explanation of how acetylation regulates these processes. Given that the mode of cell death may be singular or coexist with two or more types in certain diseases, this article aims to conduct an in-depth analysis of the regulatory role of a specific PTM of proteins (acetylation) on different cell death pathways. Furthermore, it seeks to summarize potential key pathways or targets through which acetylation influences the interplay of various cell death mechanisms. By intervening in multiple cell death pathways, this study aims to provide insights for the prevention and treatment of tumors and cardiovascular diseases, both of which are closely related to outcomes associated with cell death.

Glioblastoma stands as the deadliest primary brain malignancy in adults, primarily due to its resistance to conventional treatments and the restrictive nature of the blood-brain barrier (BBB). Cisplatin (CDDP), a widely used chemotherapeutic, demonstrates limited efficacy against glioblastoma owing to systemic toxicity and insufficient BBB penetration. To overcome these hurdles, we tested the platinum(II) complex [Pt(O,O'-acac)(γ-acac)(DMS)], indicated as Pt(acac)₂(DMS), known for its improved lipophilicity, ability to disrupt mitochondrial function, and reduced neurotoxic profile. Compared to CDDP, Pt(acac)₂(DMS) induced a targeted and prolonged cytotoxic response in U251 glioblastoma cells, promoting mitochondrial dysfunction, cell cycle arrest, and modulation of autophagy, while sparing primary human astrocytes. Our findings indicate that Pt(acac)₂(DMS) may overcome key limitations of cisplatin, including toxicity issues and resistance associated with autophagic adaptation, highlighting its promise as a potential therapeutic candidate for glioblastoma treatment.

Lung adenocarcinoma (LUAD) remains a major global health issue characterized by high incidence and mortality rates. RecQ-like helicase 4 (RECQL4), a member of the DNA helicase family, plays a crucial role in DNA replication, DNA damage repair, and tumor progression. However, its involvement and specific molecular mechanisms in LUAD progression have not been elucidated. Through this investigation, we found that RECQL4 expression was aberrantly elevated in clinical LUAD tissues, and higher levels of RECQL4 expression were associated with poor prognosis and worse clinicopathological characteristics in LUAD patients. Gain-of-function and loss-of-function studies demonstrated that RECQL4 promoted the proliferation, migration, and invasion abilities of LUAD cells. Subsequent gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis confirmed that RECQL4 activates the NF-κB signaling pathway. Mechanistic investigation indicated that RECQL4 might function as a scaffold protein for the Y box binding protein 1 (YBX1) and GTPase-activating protein SH3 domain-binding protein 1 (G3BP1), enhancing the interaction between YBX1 and G3BP1, thereby activating the NF-κB signaling pathway and promoting the progression of LUAD. In conclusion, RECQL4 promotes the malignant progression of LUAD through the YBX1/G3BP1-mediated NF-κB signaling pathway. These findings suggest that RECQL4 has the potential to serve as a novel prognostic biomarker and an effective therapeutic target for LUAD.

Breast cancer (BC) is the most prevalent malignant disease affecting female patients globally, with triple-negative breast cancer (TNBC) being the subtype linked to the poorest clinical outcome. The liver is a frequent metastatic site of breast cancer. Therefore, elucidating the mechanism underlying liver metastasis in TNBC is crucial for identifying effective diagnostic and therapeutic targets, which holds significant potential for guiding clinical treatment. This study aimed to identify key genes driving breast cancer liver metastasis and to explore their functional mechanisms. Using RNA sequencing of metastatic 4T1-HM3 and primary 4T1-Pri tumor cells, mesothelin (MSLN) was identified as significantly upregulated in metastatic TNBC cells and tissues, as confirmed by qRT-PCR, Western blot, and immunohistochemistry. Further investigations revealed that MSLN overexpression is strongly correlated with liver metastasis compared to metastases at other sites. Mechanistically, MSLN binds to epidermal growth factor receptor (EGFR) and activates the EGFR-ERK1/2 signaling axis, thereby promoting TNBC cell survival and proliferation during metastasis. Importantly, targeting MSLN with a paclitaxel/carboplatin combination effectively inhibited liver metastasis of hepatotropic TNBC in a mouse model. Therefore, our study elucidates the role of the MSLN-mediated EGFR-ERK1/2 signaling pathway in TNBC liver metastasis and highlights potential targeted therapies for treating TNBC liver metastasis.

The aryl hydrocarbon receptor (AHR) is a transcription factor prominently expressed at barrier sites, while aldehyde dehydrogenase 3 family member A1 (ALDH3A1) is a metabolic enzyme implicated in oxidative stress. However, their roles in ferroptosis remain poorly understood. Imperatorin (IMP) is a bioactive compound derived from traditional Chinese medicine. Here, we demonstrate that IMP is a natural agonist of AHR, inhibiting LPS-induced ferroptosis, inflammation, and barrier damage in lung epithelial cells by promoting AHR nuclear translocation and activation. Mechanistically, IMP-activated AHR stimulated the Nrf2/HO-1/GPX4 axis and enhanced ALDH3A1 expression, thereby inhibiting ferroptosis-related Fe²⁺ accumulation, ROS production, and lipid peroxidation. The in vivo results showed that oral IMP activated the AHR/ALDH3A1 and Nrf2/HO-1/GPX4 pathways in lung tissue, thus improving lung dysfunction and inflammation in acute lung injury (ALI) mice induced by LPS. Notably, ALDH3A1 is a key downstream signaling protein of AHR. An AHR inhibitor reversed the IMP-induced upregulation of ALDH3A1, whereas an ALDH3A1 inhibitor blocked the anti-ferroptotic Nrf2/HO-1/GPX4 pathway and diminished the lung-protective effects of IMP-activated AHR both in vitro and in vivo. These findings indicate that the AHR/ALDH3A1 axis may represent a previously unrecognized therapeutic target for ferroptosis and provide insight into IMP as a therapeutic strategy to prevent and treat ALI.

Recent studies have shown that heat shock protein 90 alpha family class A member 1 (HSP90AA1) interacts with various tumor-associated proteins, regulates their biological activity and stability, and plays an important role in various tumors. However, the role of HSP90AA1 in clear cell renal cell carcinoma (ccRCC) remains unclear. In the study, GEO and TCGA-KIRC databases were used to analyze the expression pattern and clinical significance of HSP90AA1 in ccRCC; immunohistochemistry and Western blot were used to validate HSP90AA1 expression in ccRCC tissues and cell lines; colony formation assays, EdU and TUNEL methods, cell migration and invasion experiments, and a mouse renal orthotopic xenograft tumor model were used to detect the effects of HSP90AA1 overexpression on the biological function of ccRCC; Co-IP and RNA-seq experiments were utilized to explore the downstream regulatory mechanism of HSP90AA1. Our results showed that HSP90AA1 expression was significantly downregulated in ccRCC, and its reduced expression was associated with tumor metastasis. HSP90AA1 overexpression markedly inhibited the proliferation and metastasis ability of ccRCC cells. HSP90AA1 bound to F-box only protein 7 (FBXO7) and accelerated its protein expression. FBXO7 was expressed at low level in ccRCC, and its decreased expression was closely related to unfavorable pathological features of tumors and poor patient prognosis. FBXO7 overexpression promoted cell adhesion molecule 1 (CADM1) expression and suppressed the PI3K-AKT signaling pathway. Knocking down FBXO7 expression on the basis of HSP90AA1 overexpression significantly reversed the cell phenotype inhibition caused by HSP90AA1 overexpression, downregulated CADM1 expression, and activated the PI3K-AKT signaling pathway. In summary, HSP90AA1 exhibited a low expression pattern in ccRCC, and HSP90AA1 overexpression promoted CADM1 expression and inhibited the PI3K-AKT pathway, thereby suppressing the proliferation and metastasis of ccRCC.

In the present study, we aimed to investigate the antioxidant and therapeutic protective effects of carvacryl acetate (CAA) on Mitochondrial damage of cerebral ischemia-reperfusion through mitochondrial transcription factor A (TFAM) signaling molecules.SD rats were used to establish the middle cerebral artery occlusion (MCAO) model in vivo, and PC12 cells were stimulated with H₂O₂ in vitro. Longa neurological score and triphenyltetrazolium chloride (TTC) staining was used to observe the ischemic infarction. Transmission electron microscope (TEM) was used to observe the mitochondria. Reactive Oxygen Species/ Superoxide Dismuptase/Malondialdehyde/Adenosine Triphosphate (ROS/SOD/MDA/ATP) detection kit was used to detect. RT-qPCR was used to detect the mRNA level of target gene and mitochondrial DNA (mtDNA) copy number changes. Immunofluorescence and Western blot were used to detect the expression of protein. After oxidative stress in the MCAO model of SD rats, the neurological score increased, the volume of ischemic area of cerebral infarction increased, the morphology of nerve cells in brain tissue and PC12 cells was disordered, the mitochondria appeared vacuolated, the contents of ROS and MDA increased, and the activity of SOD decreased. Oxidative stress causes mitochondrial dysfunction, resulting in the reduction of mtDNA copy number and the decreased expression of TFAM in brain tissue nerve cells and PC12 cells, which in turn affects mitochondrial transcription biogenesis and decreases the expression of POLRMT and TFB₂M molecules. CAA promotes intracellular TFAM expression and activates its antioxidant pathway, thereby protecting mtDNA and alleviating oxidative stress and mitochondrial damage caused by MCAO in vivo and H₂O₂ stimulation in vitro. Lentivirus downregulates the expression of TFAM, and under its action, the antioxidant and mitochondrial protection effects of CAA are weakened. When TFAM was disrupted, the protective effect of CAA on mitochondria was inhibited. Compared to edaravone, a positive control, CAA exhibited similar therapeutic effects. These findings suggest that CAA alleviates CIRI through TFAM signaling pathways, offering potential therapeutic implications for ischemic stroke treatment.

Prostate cancer (PCa) patients with bone metastasis commonly exhibit osteoblastic-type and have an extremely poor prognosis. Exosomes derived from tumor cells possess biological significance and can mediate intercellular communication in the tumor microenvironment. Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) is implicated in tumorigenesis and the development of PCa, but the precise roles of SNHG1 in the regulation of bone homeostasis remain elusive. Herein, we aimed to investigate the underlying mechanisms by which exosomes-encapsulated SNHG1 affects the bone metastasis of PCa. Our findings revealed that SNHG1 was overexpressed in PCa tissues, highly enriched in PCa cell-derived exosomes, and positively correlated with bone metastasis. Besides, SNHG1 shuttled by PCa-derived exosomes could be transferred into osteoblast cells, where SNHG1 exerted inductive properties in osteogenic differentiation. Gain- and loss-of-functional experiments demonstrated that exosomal SNHG1 facilitated the activity of alkaline phosphatase and mineralization of extracellular matrix. Moreover, in vivo experimentation showed that knockdown of exosomal SNHG1 suppressed bone metastasis of PCa cells. Mechanistic investigations revealed that exosomal SNHG1, transmitted to osteoblast cells, physically binds to YBX1 and leads to the shift of YBX1 into the nucleus, then enhances MMP16 transcription and increases the amount of protein translation, ultimately resulting in PCa bone metastasis. In conclusion, our data highlight that PCa-derived exosomes-loaded SNHG1 mediated osteogenesis through the SNHG1/YBX1/MMP16 axis. SNHG1 may serve as a potential diagnostic marker and therapeutic target for bone metastasis in PCa.

This study examines hypoxia's role in regulating ATXN3 (ATXN3) across cervical cancer subtypes and its impact on tumor progression. We analyzed ATXN3 expression in clinical samples and cell lines (C33A, HeLa, SiHa), assessing proliferation/migration/invasion after ATXN3 modulation. The study investigated whether ATXN3 is regulated by hypoxia through hypoxia-inducible factor 1α (HIF-1α). Downstream mechanisms were explored using clinical samples and cell lines, comparing P53 and signal transducer and activator of transcription 5 (STAT5)/p-STAT5 levels between cancer tissues and adjacent non-cancerous tissues, and assessing changes following ATXN3 manipulation. ATXN3 was downregulated in human papillomavirus(HPV18⁺) cervical adenocarcinoma but upregulated in HPV16⁺ cervical squamous cell carcinoma. ATXN3 suppressed malignant behaviors in C33A and HeLa but promoted them in SiHa. HIF-1α expression was elevated in cancer tissues versus non-cancerous tissues, with hypoxic conditions differentially regulating ATXN3 via HIF-1α across cell lines. Cervical cancer tissues showed lower P53 and higher p-STAT5 (in HPV16+ squamous cell carcinoma). ATXN3 overexpression stabilized P53 in C33A/HeLa and increased p-STAT5 in SiHa, with inverse effects upon silencing. The findings suggest that hypoxia promotes the progression of subtypes of cervical cancer by regulating ATXN3-enhanced P53/p-STAT5 levels, which may provide a novel therapeutic strategy for clinical applications.