Cell Death Discovery最新文献

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.

Hypertension is a highly prevalent chronic disease all around the world, and the pathogenic mechanism is complicated. The early and rapid decline of the function of human vascular system due to the aging of human body are characteristics of hypertension, which is accompanied by progressive pathological remodeling and arterial stiffening. The pathogenetic action of oxidation and inflammation is the vital function in the process of endothelial dysfunction and arterial injury. Bone marrow is considered as the birthplace of the immune cell, and the role of bone marrow in hematopoiesis and immune response for the onset of hypertension has been confirmed. In turn, inflammatory and oxidative stress also affect the bone marrow and damage bone marrow function, causing a series of complications in hypertension, resulting in a vicious cycle. Recently, increasing evidence has suggested that bone marrow aging plays an important role in the onset and development of hypertension, and that the function of bone marrow in the pathogenesis of hypertension has been seriously overlooked. Bone marrow microvascular ageing is also involved in the progression of bone marrow ageing. Thus, this review mainly focuses on bone marrow function in aging and hypertension progression, addresses the current studies on the roles of vascular aging, the bone marrow and the immune system in hypertension, and discusses their interaction and function in the pathogenesis of hypertension. Furthermore, some novel molecular pathological mechanisms are surveyed. This can add a new impetus to the mechanism research of hypertension onset.

SARS-CoV-2 exploits multiple host cellular processes, including autophagy, a critical intracellular degradation pathway, to facilitate viral replication and evade immune detection. Tetrandrine, a natural bis-benzylisoquinoline alkaloid derived from Stephania tetrandra, has been reported to modulate autophagy and exhibits potential antiviral properties. In this study, we investigated the effects of Tetrandrine on SARS-CoV-2 infection in human lung epithelial cells (Calu-3), with a particular focus on autophagy-related mechanisms. Our results demonstrate that Tetrandrine modulates autophagic activity in a dose-dependent manner and significantly reduces SARS-CoV-2 replication, particularly when administered prior to infection. Notably, its antiviral effect is retained in autophagy-deficient cells, indicating the involvement of autophagy-independent mechanisms. Proteomic analysis of Calu-3 cells infected with the Omicron BA.5 variant revealed that Tetrandrine regulates several host pathways implicated in viral replication, including autophagy, cholesterol metabolism, and insulin-like growth factor signaling. These findings suggest that Tetrandrine exerts multifaceted antiviral effects by targeting both autophagy-dependent and -independent cellular pathways. Collectively, our data supports the potential of Tetrandrine as a therapeutic candidate against COVID-19 and warns further evaluation in preclinical and clinical models. Data are available via ProteomeXchange with identifier PXD064448.

Genome-wide studies have identified the nuclear gene EPAS1 and the mitochondrial M9a haplogroup as pivotal contributors to hypoxia adaptation in Tibetans. However, the interaction between these two genetic components is not yet clear. In this study, we demonstrate that cells harboring the Tibetan-specific M9a haplogroup with downregulated EPAS1 (M9a+shEPAS1) exhibit enhanced cellular function under hypoxic conditions. These cells display improved mitochondrial function and proliferation, alongside reduced apoptosis and mtDNA-mediated inflammation, driven by the activation of HIF-1α-BNIP3/NIX-mediated mitophagy and an increase in reactive oxygen species (ROS) levels. Furthermore, treatment with N-acetylcysteine (NAC), PX-478, or Mdivi-1 significantly attenuated BNIP3/NIX-mediated mitophagy, leading to an aggravation of mtDNA-mediated inflammation and apoptosis in M9a+shEPAS1 cells during hypoxia. This study first reveals that ROS-driven HIF-1α-BNIP3/NIX-mediated mitophagy mitigates hypoxia-induced inflammation and apoptosis, contributing to the enhanced hypoxia adaptation observed in Tibetans. HIF-1α-BNIP3/NIX-mediated mitophagy may offer potential therapeutic targets for high-altitude illnesses by regulating cellular energy metabolism and inflammation.

Sepsis-induced acute lung injury (ALI) is a critical clinical condition characterized by severe inflammation and alveolar epithelial barrier disruption, with limited effective treatments. Our study investigates the role of Sbno2-expressing tissue-resident alveolar macrophages (TR-AMs) in promoting alveolar epithelial cell (AEC) regeneration and barrier function in sepsis-induced ALI. Utilizing single-cell RNA sequencing (scRNA-seq), we identified significant upregulation of Sbno2 in TR-AMs, which correlated with enhanced AEC proliferation and reduced apoptosis. Functional assays demonstrated that Sbno2-expressing TR-AMs substantially supported alveolar structure regeneration in both in vitro and in vivo models. Knockout of Sbno2 in TR-AMs impaired AEC proliferation and compromised lung barrier integrity. Therapeutic administration of recombinant Sbno2 (rSbno2) in a sepsis-induced ALI mouse model alleviated lung injury, promoted AEC proliferation, and restored barrier function, highlighting Sbno2 as a potential therapeutic target for ALI. These findings provide novel insights into the molecular mechanisms of lung repair in sepsis-induced ALI and suggest that enhancing Sbno2 expression in TR-AMs could be a promising strategy for improving outcomes in patients with ALI.

Pressure overload-induced vascular remodeling is a complex physiological response that can result in detrimental cardiovascular diseases. Ubiquitination plays a critical role in this process; however, the role and specific mechanism of deubiquitinating enzyme USP13 in vascular remodeling remain poorly understood. Male C57BL/6J mice were subjected to pressure overload via transverse aortic constriction to investigate USP13's effects in arterial remodeling. Primary vascular smooth muscle cells (VSMCs) were employed to investigate the role of USP13 on VSMC phenotype transition and potential mechanism. Mechanical stretch increased USP13 protein levels in vascular tissues while downregulating Acta2. Similarly, in both rat and human aortic VSMCs, PDGF-BB treatment significantly raised USP13 mRNA and protein levels. Notably, USP13 overexpression worsened arterial wall thickening in TAC mice and decreased Acta2 levels, whereas Spautin-1 treatment had a protective effect. At the cellular level, knocking down USP13 mitigated PDGF-BB-induced VSMC proliferation, as indicated by lower PCNA levels and reduced EdU (+) cell counts. Additionally, USP13 overexpression enhanced VSMC migration, demonstrated by scratch and transwell experiments. USP13 also aggravated PDGF-BB-induced downregulation of ACTA2 and Transgelin while promoting OST elevation. Mechanistically, USP13 interacted with Beclin-1, facilitating its deubiquitination and promoting autophagic flux, as shown by increased LC3 II/I ratios and decreased p62 levels. Moreover, BHLHE40 was explored as a new transcription factor of USP13, and BHLHE40 can regulate VSMCs proliferation and migration by transcriptionally activating USP13. In conclusion, our findings elucidate the role of USP13 in vascular remodeling under pressure overload, suggesting that targeting USP13 may offer therapeutic potential for pathological vascular disorders.

Recently, various attenuated bacteria have been studied as cancer therapies due to their unique characteristics, which include tumor-targeting bioactivity and immunogenicity. Previously, we reported a Salmonella typhimurium strain, CNC018, which is attenuated by 10⁵-10⁶-fold compared with the wild-type strain but retains tumor-targeting specificity. However, although these bacteria suppress tumors at the early stage in mice, the tumors often regrow at later stages. Therefore, to increase antitumor efficacy, we used a doxycycline-inducible system to engineer this strain (CNC018pCH) to secrete both cytolysin A (ClyA) and hyaluronidase (HysA), a pore-forming toxin that kills tumor cells and an enzyme that disrupts the tumor microenvironment, respectively. Local secretion of ClyA from CNC018pCH triggered tumor cell death through pyroptosis, apoptosis, and necrosis (PANoptosis) in a cholesterol-dependent manner, thereby releasing cellular contents and danger signals to activate the immune system. In addition, localized secretion of HysA degraded hyaluronic acid secreted by cancer cells, facilitated bacterial penetration into tumors, and inhibited metastasis by down-regulating the ribosomal S6 kinase (RSK)-related signaling pathway. These therapeutic payloads enhanced the ability of S. typhimurium to control tumor growth and metastasis in various murine tumor models. Notably, CNC018pCH also generated memory responses by protecting cured mice from tumor rechallenge. Taken together, these findings demonstrate that this engineered bacterium is a promising candidate for cancer treatment by reshaping the tumor microenvironment through the induction of tumor cell death and degradation of hyaluronic acid.

Metabolic reprogramming of vascular smooth muscle cells (VSMC) is emerging as a central driver of atherosclerotic plaque heterogeneity and instability. VSMCs undergo phenotypic remodeling into osteogenic, macrophage-like, foam cell-like, or pro-inflammatory states through metabolic reprogramming, which actively drives vascular calcification, lipid accumulation, and extracellular matrix degradation. In this review, we summarize the various phenotypes of VSMCs observed during AS development and describe potential molecular pathways linking metabolic reprogramming to phenotypic remodeling. We highlight key regulators, including glucose transporters, pyruvate dehydrogenase kinase 4, 6 - Phosphofructo - 2 - kinase/fructose - 2, 6 - bisphosphatase 3, pyruvate kinase M2, fatty acid synthase, homocysteine, etc., which integrate extracellular stimuli and intracellular metabolic changes to drive VSMCs fate decisions. In addition, we discuss how specific metabolic pathways interact with epigenetic and signaling networks to regulate VSMCs proliferation, apoptosis, calcification, foaming, and aging. Finally, we explore therapeutic opportunities for targeted metabolic regulators, including traditional Chinese medicine, Sirtuin 1 activators, ATP-Citrate Lyase inhibitors, statins, folic acid, etc., providing new strategies to stabilize plaques and slow the progression of AS.

Monomethyl fumarate (MMF), the active metabolite of dimethyl fumarate, an immunomodulatory drug approved for multiple sclerosis and psoriasis, has emerging potential in ischemic heart disease. We investigated whether MMF can attenuate myocardial infarction (MI) injury and delineated the underlying mechanisms, focusing on hydroxycarboxylic acid receptor 2 (HCAR2, also known as GPR109A) and PI3K/Akt signaling. In a mouse MI model induced by permanent left anterior descending coronary artery ligation, MMF administration prior to ischemia significantly preserved left ventricular function and reduced cardiomyocyte apoptosis compared with untreated MI. Echocardiography and pressure-volume loop analyses demonstrated higher ejection fraction and cardiac output in MMF-treated MI mice, accompanied by attenuation of adverse ventricular remodeling. TUNEL staining and analysis of apoptotic markers showed that MMF decreased myocardial cell death and caspase-3 activation in vivo, while concomitantly upregulating HCAR2 expression and enhancing Akt phosphorylation in ischemic myocardium. In vitro, MMF protected HL-1 cardiomyocytes from CoCl₂-induced hypoxic injury, improving cell viability and reducing apoptosis, as evidenced by fewer TUNEL-positive cells and a lower Bax/Bcl-2 ratio compared with hypoxia alone. Pharmacological inhibition of Gi-coupled signaling with pertussis toxin or siRNA-mediated knockdown of HCAR2 abolished MMF's cytoprotective effects and blunted MMF-induced Akt phosphorylation, and PI3K/Akt pathway inhibition eliminated MMF's anti-apoptotic benefits in vitro. Collectively, these findings demonstrate that MMF markedly reduces ischemic cardiomyocyte injury via an HCAR2-dependent mechanism involving activation of the pro-survival PI3K/Akt pathway, establishing a novel cardioprotective role for MMF and supporting its translational potential as a therapeutic strategy to mitigate acute MI injury.