Cell Biology and Toxicology最新文献

Breast cancer (BC) is the most frequently diagnosed malignancy among women worldwide, with a high incidence and mortality rate. Despite advances in treatment, approximately 10%-15% of patients with BC still face recurrence. Therefore, improving BC therapy remains a significant challenge. In this article, we provide a detailed overview, categorizing and elaborating the developments of current research progress on nanodrug delivery systems based on ferroptosis for BC treatment. By increasing the iron content in BC cells and inhibiting the defense system against ferroptosis, the accumulation of lipid peroxides is promoted, and ferroptosis is induced in BC cells. In addition to directly targeting tumor cells, nanodrug delivery systems can remodel the tumor microenvironment, inhibit BC primary growth, and prevent distant metastasis. These nanomaterials, after drug loading and modification, possess characteristics such as smart activation, controlled release, specific targeting, good biocompatibility, and long circulation time, thereby enhancing the efficacy of BC treatment. We also classify and discuss the mechanisms and advantages of different types of nanomaterials. Finally, we discuss how multifunctional nanosystems can sensitize ferroptosis when combined with radiotherapy, chemotherapy, immunotherapy, and phototherapy to achieve synergistic effects in BC treatment. This work reveals the potential of ferroptosis-based nanomaterials in overcoming BC, analyzes the limitations of the clinical application and proposes possible solutions, offering a promising direction for future treatment strategies.

Age-related macular degeneration (AMD) has been well recognized as the first ranked blinding ocular fundus diseases among older individuals, particularly in developed regions, owing to its progressive nature and high prevalence in aging populations. Anti-vascular endothelial growth factor (VEGF) agents injected into patients' vitreous cavity is the preferred treatment regimen for neovascular AMD. However, many patients exhibit resistance to anti-VEGF treatment, which is an urgent clinical problem. In this study, we treated mouse and endothelial cells with anti-VEGF drug Ranibizumab and stromal cell-derived factor-1α (SDF-1α) and found that ferroptosis was induced by Ranibizumab but inhibited by SDF-1α. SDF-1α inhibited ferroptosis by promoting transport of Sterol regulatory element binding protein 1 (SREBP1) from endoplasmic reticulum (ER) to Golgi transportation and SREBP1 maturation. Furthermore, we found that metadherin (MTDH) mediates SREBP1' s movement from the endoplasmic reticulum (ER) to Golgi apparatus by inhibiting SREBP1 binding to INSIG1/INSIG2. Our study revealed the important role of SDF-1α/MTDH/SREBP1 axis in regulating anti-VEGF treatment resistance in patients with AMD.

Tamoxifen is a critical drug for the treatment of oestrogen receptor (ER)-positive breast cancer (BC), which represents the majority of BC subtypes. However, many BC tumours that initially respond eventually develop acquired Tamoxifen resistance. Bioinformatics analysis was conducted on genes affected by Tamoxifen and upregulated in Tamoxifen-resistant cells to identify the biological processes associated with Tamoxifen resistance. Metabolomics analysis was conducted to identify the metabolites that were altered in BC with tamoxifen resistance. Resistance to Tamoxifen was evaluated by cell viability, proliferation, invasion, and colony formation in vitro, and by tumour growth in vivo. Metabolomic profiling and the detection of relevant enzymes and metabolites corroborated the metabolic reprogramming towards glycolysis in tamoxifen - resistant BC. The produced lactic acid induced the lactylation of ZMIZ1. This post-translational modification at K843 (but not K537) increased protein stability by suppressing SUMOylation and ubiquitination. The elevated total level of ZMIZ1 increased the enrichment of ZMIZ1 binding to Nanog, resulting in increased transcriptional activity of Nanog, including in OCT4 and NPC2 genes. Therefore, it leads to increased stemness and cholesterol accumulation in Tamoxifen-resistant BC. Knockdown of ZMIZ1 impaired Tamoxifen resistance, but this effect was reversed by Nanog overexpression. In summary, this study identified an important mechanism underlying Tamoxifen resistance and revealed a potential association of glucose glycolysis with cholesterol metabolism through the ZMIZ1/Nanog/NPC2 axis.

The burgeoning field of epigenetics holds considerable potential in cancer prevention and management, as it targets mechanisms essential to regulating gene expression without altering DNA sequences. Epigenetic processes like DNA methylation, histone modifications, non-coding RNAs, and nucleosome remodelling-play an essential role in cellular differentiation and development, with dysfunction in these pathways often leading to malignancy. Targeting epigenetic regulators, including DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), can suppress cancer cell proliferation, making epigenetics a promising therapeutic frontier. Phytochemicals, natural bioactive compounds predominantly found in vegetables, fruits, and seeds, offer a complementary approach to traditional cancer therapies through their epigenetic influence. These compounds exhibit anti-inflammatory, anti-angiogenic, and antioxidant properties, which modulate pathways and proteins involved in chromatin remodeling and may influence the mammalian epigenome. A diverse spectrum of bioactive dietary ingredients, including curcumin, epigallocatechin-3-gallate (EGCG), genistein, quercetin, resveratrol, and sulforaphane, has gained significant interest for their ability to modulate gene expression and chromatin structure via epigenetic mechanisms. Their potential implications for cancer prevention and their role in regulating key epigenetic genes have been described in numerous investigations. This comprehensive review explores the molecular mechanisms by which dietary bioactive molecules may reverse epigenetic aberrations in cancer cells. It examines the influence of these compounds on DNA methylation, ten-eleven translocation (TET) enzymes, and histone modifications, while discussing their specific molecular targets in various cancer types. Additionally, we highlight the pathways through which these epi-nutrients may impact gene expression and enzyme activities associated with epigenetic regulation, which leads to innovative, diet-based anticancer strategies. Clinical trial number: not applicable.

Hybrid hydrogels have emerged as multifunctional biomaterials for targeted drug delivery and tissue engineering in gynecologic oncology. In this review, we summarize recent advances in the design of hybrid hydrogels that combine polymer networks with nanomaterials to achieve tunable stimuli-responsiveness, enhanced mechanical strength, and improved biocompatibility. For example, preclinical studies of folate-conjugated liposomal doxorubicin have demonstrated enhanced accumulation and antitumor efficacy in ovarian cancer models, while growth factor-loaded hydrogel scaffolds have supported endometrial repair in rodent models. We discuss strategies for optimizing drug loading, controlling spatiotemporal release profiles in response to tumor-specific cues (such as pH or enzyme activity), and customizing scaffold architecture for patient-specific regenerative needs. Implementation challenges-including efficient encapsulation of multiple cargos, precise control over degradation rates, and scale-up for clinical manufacturing-are critically examined. Finally, we outline future directions, including multifunctional platforms that integrate real-time monitoring with combined chemo-immunotherapy and approaches to address regulatory and translation hurdles. This evidence-based analysis highlights how hybrid hydrogels can advance precision therapy and regenerative medicine for gynecologic cancers while there is a need for further validation in clinical settings.

Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C_LTMR following paclitaxel treatment. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. Additionally, Camk1d is involved in temperature hyperalgesia in CIPN, a key clinical symptom observed in human patients with CIPN. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.

Sepsis is clinically defined as a life-threatening syndrome characterized by dysregulated host responses to infection, culminating in progressive multi-organ dysfunction. The pathogenesis of sepsis-associated organ dysfunction (SAOD) -manifesting as encephalopathy, cardiomyopathy, acute kidney/liver injury, and respiratory failure-represents the primary determinant of mortality in septic patients. Despite its clinical significance, the molecular mechanisms driving SAOD remain incompletely elucidated. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis is a critical innate immune pathway by triggering a type I interferon (IFN-I) response. However, aberrant activation of this axis leads to inflammatory and autoimmune diseases.Emerging evidence implicates hyperactivation of cGAS-STING as a critical mediator of SAOD across multiple organ systems. Notably, pharmacological inhibitors targeting cGAS-STING signaling demonstrate therapeutic promise in preclinical models of sepsis-induced organ injury, attenuating inflammatory cascades and preserving tissue integrity. This review synthesizes current insights into the mechanistic contributions of cGAS-STING signaling to SAOD pathogenesis while critically evaluating novel therapeutic agents-including small -molecule inhibitors, natural compounds, and biologics-that disrupt this pathway to mitigate organ dysfunction. By bridging molecular mechanisms with translational applications, we underscore cGAS-STING inhibition as a paradigm-shifting strategy for addressing the unmet clinical needs in sepsis and SAOD management.

Collagen is a central component of the extracellular matrix (ECM) in tissues, and ECM can promote tumor cell immune evasion. Our research aimed to expound the biological function of the collagen alpha-1(IX) chain (COL9A1) in colorectal cancer (CRC) and the upstream mechanism regarding KMT2D/ZNF460. COL9A1 contributed to maintaining colorectal cancer stem cells (CCSC) self-renewal and proliferative capacity, and COL9A1 knockdown attenuated CCSC stemness, which was activated by 20.0 kPa polyacrylamide gels. Silencing of COL9A1 hampered tumor growth and stemness in mice induced by AOM/DSS and improved the tumor microenvironment (TME) in xenograft-bearing mice. Mechanistically, KMT2D promoted COL9A1 expression by mediating H3K4me1 modification of the enhancer and recruiting ZNF460. In the presence of attenuated KMT2D signaling, its effect on CCSC stemness and CRC progression was similar to that of knockdown of COL9A1, both of which have therapeutic benefits for CRC tumors. Again, the reactivation of COL9A1 reversed this trend. In conclusion, KMT2D mediates H3K4me1 modification of enhancers and recruits ZNF460 to activate COL9A1, which enhances ECM stiffness and self-renewal of CCSC to remodel TME, contributing to CRC progression.

The rapid escalation of oxidative and nitrosative stress during ischemia/reperfusion (I/R) triggers neuronal damage, leading to severe neurological deficits and long-term disability. N6-methyladenosine (m⁶A), a highly abundant RNA modification in the brain, undergoes dynamic changes following acute I/R injury, and regulates stroke pathogenesis and neurological outcomes. However, the molecular mechanisms by which m⁶A influences acute I/R injury responses remain elusive. Our study reveals that the expression of key I/R pathogenesis pathways positively correlates with the expression of m⁶A reader proteins. Modulating expression of YTHDF1, a neuron-enriched reader protein of m⁶A, results in bidirectional changes in oxidative stress response and neuronal viability under I/R conditions. We have identified p53 mRNA as a critical target of m⁶A methylation and YTHDF1, driving the translation of p53 protein in a context- and m⁶A-dependent manner, which exacerbates oxidative stress and ferroptosis. This novel mechanism suggests the potential of targeting the m⁶A reader protein as a strategic avenue for developing neuroprotective therapies to mitigate I/R injury.

Curcumin (Cur), a natural bioactive compound extracted from Curcuma longa, has garnered extensive interest due to its modulation of inflammation, antioxidant, and anti-tumor properties. However, its therapeutic translation remains constrained by limited systemic bioavailability. Triple-negative breast cancer (TNBC), an aggressive variant of breast malignancies, exhibits strong resistance to conventional therapies and poor prognosis. The present study was designed to clarify the mechanism through which NGR-modified nanovesicles loaded with Cur (NGR-NVs@Cur) reverse immunotherapy resistance in TNBC. Using transcriptomic and network pharmacology analysis, we identified key genes involved in TNBC development and immunotherapy resistance to determine the targets of Cur. In vitro experiments, including SA-β-gal staining, flow cytometry, and glycolysis analysis, validated that TNBC cells induce glycolysis and CD8⁺ T cell senescence. NGR-NVs@Cur were successfully constructed and marked by transmission electron microscopy (TEM), dynamic light scattering (DLS), pH-responsive release, and cellular uptake assays. Further cell-based studies demonstrated that NGR-NVs@Cur suppressed TNBC cell proliferation, migration, glycolysis, and reversed CD8⁺ T cell senescence. In vivo, both subcutaneous xenograft and adoptive T cell transfer models were developed to evaluate the therapeutic effects of NGR-NVs@Cur in combination with immune checkpoint inhibitors (ICIs, e.g., J43). The results revealed that Cur inhibited TNBC cell glycolysis and T cell senescence by activating TLR9 and suppressing the mTOR pathway, and that NGR-NVs@Cur enhanced targeted Cur delivery and effectively reversed immunotherapy resistance. This study demonstrated a novel strategy by which Cur, delivered via tumor-targeted nanovesicles, modulates glycolysis and CD8⁺ T cell senescence through the TLR9-mTOR axis, offering promising insights into overcoming immune resistance in TNBC.