Natural products as glycolytic inhibitors for cervical cancer treatment: A comprehensive review.

Cervical cancer, a prevalent gynaecological malignancy, presents challenges in late-stage treatment efficacy. Aerobic glycolysis, a prominent metabolic trait in cervical cancer, emerges as a promising target for novel drug discovery. Natural products, originating from traditional medicine, represent a significant therapeutic avenue and primary source for new drug development. This review explores the regulatory mechanisms of glycolysis in cervical cancer and summarises natural compounds that inhibit aerobic glycolysis as a therapeutic strategy. The glycolytic phenotype in cervical cancer is regulated by classical molecules such as HIF-1, HPV virulence factors and specificity protein 1, which facilitate the Warburg effect in cervical cancer. Various natural products, such as artemisinin, shikonin and kaempferol, exert inhibitory effects by downregulating key glycolytic enzymes through signalling pathways such as PI3K/AKT/HIF-1α and JAK2/STAT3. Despite challenges related to drug metabolism and toxicity, these natural compounds provide novel insights and promising avenues for cervical cancer treatment.

Ferroptotic therapy in cancer: benefits, side effects, and risks.

Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation.

Alkaliptosis induction counteracts paclitaxel-resistant ovarian cancer cells via ATP6V0D1-mediated ABCB1 inhibition.

Paclitaxel serves as the cornerstone chemotherapy for ovarian cancer, yet its prolonged administration frequently culminates in drug resistance, presenting a substantial challenge. Here we reported that inducing alkaliptosis, rather than apoptosis or ferroptosis, effectively overcomes paclitaxel resistance. Mechanistically, ATPase H+ transporting V0 subunit D1 (ATP6V0D1), a key regulator of alkaliptosis, plays a pivotal role by mediating the downregulation of ATP-binding cassette subfamily B member 1 (ABCB1), a multidrug resistance protein. Both ATP6V0D1 overexpression through gene transfection and pharmacological enhancement of ATP6V0D1 protein stability using JTC801 effectively inhibit ABCB1 upregulation, resulting in growth inhibition in drug-resistant cells. Additionally, increasing intracellular pH to alkaline (pH 8.5) via sodium hydroxide application suppresses ABCB1 expression, whereas reducing the pH to acidic conditions (pH 6.5) with hydrochloric acid amplifies ABCB1 expression in drug-resistant cells. Collectively, these results indicate a potentially effective therapeutic strategy for targeting paclitaxel-resistant ovarian cancer by inducing ATP6V0D1-dependent alkaliptosis.

Factors which can influence elastic stable intramedullary nailing removal in healed bone cysts in children.

Elastic stable intramedullary nailing (ESIN) internal fixation is used clinically to treat pathological fractures of bone cysts in children. However, one of the most important complications was removal difficulty. In this study, we aim to analyse the factors which can influence ESIN removal in healed bone cysts in children. From April 2014 to November 2020, the clinical data of 49 children who underwent elastic stable intramedullary nail removal for pathological fractures of the bone cysts in our hospital were retrospectively analysed. The following data, including age, sex, pathological fracture site, with bone graft, number of ESINs, ESIN indwelling time, and extraosseous length of ESIN were collected, and univariate analysis and logistic regression analysis was performed. The frequency of difficulty in ESIN extraction was 44.90% (22/49). The univariate logistic regression analysis showed that age,ESIN indwelling time,with bone garft and extraosseous length of ESIN may be correlated with the difficulty in removing ESIN (P < 0.05), while sex, pathological fracture site, number of ESIN may not be correlated with the difficulty in removing ESIN (P > 0.05).The multivariate logistic regression analysis showed that the ESIN indwelling time was the independent influencing factor for difficulty in removing ESIN (P < 0.05). The factors influencing the ESIN removal in healed bone cysts in children include over 11.79 years old, the long indwelling time of the ESIN(over 10.5 months),with bone graft and short extraosseous length of ESIN(≤ 0.405 cm). These factors influencing ESIN removal in healed bone cysts in children should be considered.

The interaction of platelet-related factors with tumor cells promotes tumor metastasis.

Platelets not only participate in thrombosis and hemostasis but also interact with tumor cells and protect them from mechanical damage caused by hemodynamic shear stress and natural killer cell lysis, thereby promoting their colonization and metastasis to distant organs. Platelets can affect the tumor microenvironment via interactions between platelet-related factors and tumor cells. Metastasis is a key event in cancer-related death and is associated with platelet-related factors in lung, breast, and colorectal cancers. Although the factors that promote platelet expression vary slightly in terms of their type and mode of action, they all contribute to the overall process. Recognizing the correlation and mechanisms between these factors is crucial for studying the colonization of distant target organs and developing targeted therapies for these three types of tumors. This paper reviews studies on major platelet-related factors closely associated with metastasis in lung, breast, and colorectal cancers.

Ethylene controls three-dimensional growth involving reduced auxin levels in the moss Physcomitrium patens.

The conquest of land by plants was concomitant with, and possibly enabled by, the evolution of three-dimensional (3D) growth. The moss Physcomitrium patens provides a model system for elucidating molecular mechanisms in the initiation of 3D growth. Here, we investigate whether the phytohormone ethylene, which is believed to have been a signal before land plant emergence, plays a role in 3D growth regulation in P. patens. We report ethylene controls 3D gametophore formation, based on results from exogenously applied ethylene and genetic manipulation of PpEIN2, which is a central component in the ethylene signaling pathway. Overexpression (OE) of PpEIN2 activates ethylene responses and leads to earlier formation of gametophores with fewer gametophores produced thereafter, phenocopying ethylene-treated wild-type. Conversely, Ppein2 knockout mutants, which are ethylene insensitive, show initially delayed gametophore formation with more gametophores produced later. Furthermore, pharmacological and biochemical analyses reveal auxin levels are decreased in the OE lines but increased in the knockout mutants. Our results suggest that evolutionarily, ethylene and auxin molecular networks were recruited to build the plant body plan in ancestral land plants. This might have played a role in enabling ancient plants to acclimate to the continental surfaces of the planet.

Lidocaine effects on neutrophil extracellular trapping and angiogenesis biomarkers in postoperative breast cancer patients with different anesthesia methods: a prospective, randomized trial.

BACKGROUND: Anesthesia techniques and drug selection may influence tumor recurrence and metastasis. Neutrophil extracellular trapping (NETosis), an immunological process, has been linked to an increased susceptibility to metastasis in individuals with tumors. Furthermore, recurrence may be associated with vascular endothelial growth factor A (VEGF-A), a mediator of angiogenesis. This study investigates the impact of lidocaine (combined with sevoflurane or propofol anesthesia ) during breast cancer surgery inhibits the expression of biomarkers associated with metastasis and recurrence (specifically H3Cit, NE, MPO, MMP-9 and VEGF-A). METHODS: We randomly assigned 120 women undergoing primary or invasive breast tumor resection to receive one of four anesthetics: sevoflurane (S), sevoflurane plus i.v. lidocaine (SL), propofol (P), and propofol plus i.v. lidocaine (PL). Blood samples were collected before induction and 3 h after the operation. Biomarkers associated with NETosis (citrullinated histone H3 [H3Cit], myeloperoxidase [MPO], and neutrophil elastase [NE]) and angiogenesis were quantified using enzyme-linked immunosorbent assays. RESULTS: Patient and breast tumor characteristics, along with perioperative management, did not differ between study groups. In intra-group comparisons, S and P groups demonstrated a statistically significant increase in post-operative MPO (S group: 10.39[6.89-17.22] vs. 14.31[8.55-20.87] ng ml-1, P = 0.032; P group: 9.45[6.73-17.37] vs. 14.34[9.87-19.75] ng ml-1, P = 0.035)and NE(S group: 182.70[85.66-285.85] vs. 226.20[91.85-391.65] ng ml-1, P = 0.045; P group: 154.22[97.31-325.30] vs. 308.66[132.36-483.57] ng ml-1, P = 0.037) concentrations compared to pre-operative measurements, whereas SL and PL groups did not display a similar increase. H3Cit, MMP-9, and VEGF-A concentrations were not significantly influenced by the anesthesia techniques and drugs. CONCLUSIONS: Regardless of the specific technique employed for general anesthesia, there was no increase in the postoperative serum concentrations of MPO and NE after perioperative lidocaine infusion compared to preoperative serum concentrations. This supports the hypothesis that intravenous lidocaine during cancer surgery aimed at achieving a cure may potentially decrease the likelihood of recurrence. Further interpretation and discussion of clinical implications are warranted, emphasizing the significance of these findings in the context of cancer surgery and recurrence prevention. CLINICAL TRIAL REGISTRATION: ChiCTR2300068563.

Development and therapeutic implications of small molecular inhibitors that target calcium-related channels in tumor treatment.

Calcium ion dysregulation exerts profound effects on various physiological activities such as tumor proliferation, migration, and drug resistance. Calcium-related channels play a regulatory role in maintaining calcium ion homeostasis, with most channels being highly expressed in tumor cells. Additionally, these channels serve as potential drug targets for the development of antitumor medications. In this review, we first discuss the current research status of these pathways, examining how they modulate various tumor functions such as epithelial-mesenchymal transition (EMT), metabolism, and drug resistance. Simultaneously, we summarize the recent progress in the study of novel small-molecule drugs over the past 5 years and their current status.

R-loop and diseases: the cell cycle matters.

The cell cycle is a crucial biological process that is involved in cell growth, development, and reproduction. It can be divided into G1, S, G2, and M phases, and each period is closely regulated to ensure the production of two similar daughter cells with the same genetic material. However, many obstacles influence the cell cycle, including the R-loop that is formed throughout this process. R-loop is a triple-stranded structure, composed of an RNA: DNA hybrid and a single DNA strand, which is ubiquitous in organisms from bacteria to mammals. The existence of the R-loop has important significance for the regulation of various physiological processes. However, aberrant accumulation of R-loop due to its limited resolving ability will be detrimental for cells. For example, DNA damage and genomic instability, caused by the R-loop, can activate checkpoints in the cell cycle, which in turn induce cell cycle arrest and cell death. At present, a growing number of factors have been proven to prevent or eliminate the accumulation of R-loop thereby avoiding DNA damage and mutations. Therefore, we need to gain detailed insight into the R-loop resolution factors at different stages of the cell cycle. In this review, we review the current knowledge of factors that play a role in resolving the R-loop at different stages of the cell cycle, as well as how mutations of these factors lead to the onset and progression of diseases.

Porcine reproductive and respiratory syndrome virus infection activates ADAM17 to induce inflammatory responses.

Porcine reproductive and respiratory syndrome (PRRS), which has posed substantial threats to the swine industry worldwide, is primarily characterized by interstitial pneumonia. A disintegrin and metalloproteinase 17 (ADAM17) is a multifunctional sheddase involved in various inflammatory diseases. Herein, our study showed that PRRS virus (PRRSV) infection elevated ADAM17 activity, as demonstrated in primary porcine alveolar macrophages (PAMs), an immortalized PAM cell line (IPAM cells), and the lung tissues of PRRSV-infected piglets. We found that PRRSV infection promoted ADAM17 translocation from the endoplasmic reticulum to the Golgi by enhancing its interaction with inactive rhomboid protein 2 (iRhom2), a newly identified ADAM17 regulator, which in turn elevated ADAM17 activity. By screening for PRRSV-encoded structural proteins, viral envelope (E) and nucleocapsid (N) proteins were identified as the predominant ADAM17 activators. E and N proteins bind with both ADAM17 and iRhom2 to form ternary protein complexes, ultimately strengthening their interactions. Additionally, we demonstrated, using an ADAM17-knockout cell line, that ADAM17 augmented the shedding of soluble TNF-α, a pivotal inflammatory mediator. We also discovered that ADAM17-mediated cleavage of porcine TNF-α occurred between Arg-78 and Ser-79. By constructing a precision mutant cell line with Arg-78-Glu/Ser-79-Glu substitution mutations in TNF-α, we further revealed that the ADAM17-mediated production of soluble TNF-α contributed to the induction of inflammatory responses by PRRSV and its E and N proteins. Taken together, our results elucidate the mechanism by which PRRSV infection activates the iRhom2/ADAM17/TNF-α axis to enhance inflammatory responses, providing valuable insights into the elucidation of PRRSV pathogenesis.

Nesfatin-1 alleviates hyperoxia-induced bronchopulmonary dysplasia (BPD) via the nuclear factor-κB (NF-κB) p65 signaling pathway.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease in newborns, which severely influences the health of infants and lacks effective clinical treatment strategies. The pathogenesis of BPD is correlated to enhanced inflammation and activated oxidative stress (OS). The application of antioxidants and anti-inflammatory treatment could be hot spots for BPD treatment. Nesfatin-1, a peptide with a suppressive property against inflammation, was tested herein for its potential therapeutic value in BPD. Neonatal SD rats were stimulated with hyperoxia, followed by being intraperitoneally administered with 20 µg/kg/day Nesfatin-1 for 2 weeks. Decreased RAC value in lung tissues, increased wet weight/dry weight (W/D) pulmonary ratio and bronchoalveolar lavage fluid (BALF) proteins, elevated cytokine release in BALF, increased malondialdehyde (MDA) content, and declined superoxide dismutase (SOD) activity were observed in BPD rats, all of which were sharply mitigated by Nesfatin-1. Rat epithelial type II cells (AECIIs) were handled with hyperoxia, and then cultured with 1 and 10 nM Nesfatin-1. Reduced cell viability, elevated lactate dehydrogenase production, elevated cytokine secretion, elevated MDA content, and decreased SOD activity were observed in hyperoxia-handled AECIIs, all of which were markedly alleviated by Nesfatin-1. Furthermore, activated nuclear factor-κB (NF-κB) signaling observed in both BPD rats and hyperoxia-handled AECIIs were notably repressed by Nesfatin-1. Collectively, Nesfatin-1 alleviated hyperoxia-triggered BPD by repressing inflammation and OS via the NF-κB signaling pathway.

Elevated aerobic glycolysis driven by p62-mTOR axis promotes arsenic-induced oncogenic phenotypes in human mammary epithelial cells.

Chronic arsenic exposure is considered to increase the risk of breast cancer. p62 is a multifunctional adaptor protein that controls myriad cellular processes and is overexpressed in breast cancer tissues. Although previous studies have indicated the involvement of p62 accumulation in arsenic tumorigenesis, the underlying mechanism remains obscure. Here, we found that 0.1 µM or 0.5 µM arsenite exposure for 24 weeks induced oncogenic phenotypes in human mammary epithelial cells. Elevated aerobic glycolysis, cell proliferation capacity, and activation of p62-mTOR pathway, as indicated by increased protein levels of p62, phosphorylated-mTOR (p-mTOR) and hypoxia-inducible factor 1α (HIF1α), were observed in chronically arsenite-exposed cells, and of note in advance of the onset of oncogenic phenotypes. Moreover, p62 silencing inhibited acquisition of oncogenic phenotypes in arsenite-exposed cells. The protein levels of p-mTOR and HIF1α, as well as aerobic glycolysis and cell proliferation, were suppressed by p62 knockdown. In addition, re-activation of p­mTOR reversed the inhibitory effects of p62 knockdown. Collectively, our data suggest that p62 exerts an oncogenic role via mTORC1 activation and acts as a key player in glucose metabolism during arsenite-induced malignant transformation, which provides a new mechanistic clue for the arsenite carcinogenesis.

BPIFB1, Serving as a Downstream Effector of EBV-miR-BART4, Blocks Immune Escape of Nasopharyngeal Carcinoma via Inhibiting PD-L1 Expression.

Nasopharyngeal carcinoma (NPC) is one of the most common tumors of head and neck in the Southeast Asia. PD-L1-dependent immune escape plays a critical role involved in NPC development. BPIFB1 has previously reported to take tumor-suppressive actions on NPC cell proliferation and migration. Nonetheless, the function of BPIFB1 in immune escape remains largely elusive. Expression pattern on mRNA and protein levels of target genes in NPC patients' samples and cell lines were examined by qRT-PCR, western blot, and immunohistochemistry staining, respectively. The assessment of CD8+ T-cell apoptosis and expression was determined by flow cytometry. Molecular interactions were verified using chromatin immunoprecipitation (ChIP) and luciferase reporter assay. BPIFB1 was downregulated in NPC tumor tissues, exhibiting a negative correlation of PD-L1. Overexpression of BPIFB1 significantly inhibited the expression of PD-L1, suppressing the apoptosis and enhancing the expression of CD8+ T cells. Mechanistically, BPIFB1 was found to repress the expression of STAT1, which was identified to be an upstream activator of PD-L1. Furthermore, the EBV-encoded miR-BART4 overexpressed in NPC cells could directly target and inhibit BPIFB1. This study provided a comprehensive understanding of the molecular mechanism for the upstream and downstream pathway of BPIFB1 related with immune escape, indicating a novel approach for the treatment of NPC.

Prognostic value of different radiation-related cell death genes in patients with lung adenocarcinoma.

BACKGROUND AND AIMS: Radiotherapy is widely applied for lung adenocarcinoma (LUAD), while individualized differences led to different outcomes. This study aimed to establish a multi-gene risk scoring model to predict the benefits of LUAD patients from radiotherapy, based on different types of cell death respectively. RESULTS: Other than autophagy, pyroptosis, ferroptosis and Immunogenic cell death (ICD), the LUAD prognostic model based on apoptosis had the best performance, and the area under curves (AUCs) of the receiver operating curve (ROC) for 1-, 3-, and 5-year OS were 0.700,0.736,0.723,respectively. Such genes were involved as SLC7A5, EXO1, ABAT, NLRP1 and GAR1. Then patients were divided into high and low risk groups by the median apoptosis-LUAD risk score. For patients in the high-risk group, i.e., the radiotherapy-tolerant group, we screened adjuvant chemotherapy and found that besides the conventional first-line chemotherapy regimen, drugs such as Fludarabine, Pevonedistat, and Podophyllotoxin Bromide may also have potential therapeutic value. CONCLUSION: The multi-gene risk scoring model based on apoptosis might predict the radiotherapy benefits of LUAD patients and for those radioresistant patients classified by the model we also provided effective adjuvant chemicals, which would be used to guide clinical treatment.

Dynamic Survival Risk Prognostic Model and Genomic Landscape for Atypical Teratoid/Rhabdoid Tumors: A Population-Based, Real-World Study.

BACKGROUND: An atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon and aggressive pediatric central nervous system neoplasm. However, a universal clinical consensus or reliable prognostic evaluation system for this malignancy is lacking. Our study aimed to develop a risk model based on comprehensive clinical data to assist in clinical decision-making. METHODS: We conducted a retrospective study by examining data from the Surveillance, Epidemiology, and End Results (SEER) repository, spanning 2000 to 2019. The external validation cohort was sourced from the Children's Hospital Affiliated to Chongqing Medical University, China. To discern independent factors affecting overall survival (OS) and cancer-specific survival (CSS), we applied Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest (RF) regression analyses. Based on these factors, we structured nomogram survival predictions and initiated a dynamic online risk-evaluation system. To contrast survival outcomes among diverse treatments, we used propensity score matching (PSM) methodology. Molecular data with the most common mutations in AT/RT were extracted from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. RESULTS: The annual incidence of AT/RT showed an increasing trend (APC, 2.86%; 95% CI:0.75-5.01). Our prognostic study included 316 SEER database participants and 27 external validation patients. The entire group had a median OS of 18 months (range 11.5 to 24 months) and median CSS of 21 months (range 11.7 to 29.2). Evaluations involving C-statistics, DCA, and ROC analysis underscored the distinctive capabilities of our prediction model. An analysis via PSM highlighted that individuals undergoing triple therapy (integrating surgery, radiotherapy, and chemotherapy) had discernibly enhanced OS and CSS. The most common mutations of AT/RT identified in the COSMIC database were SMARCB1, BRAF, SMARCA4, NF2, and NRAS. CONCLUSIONS: In this study, we devised a predictive model that effectively gauges the prognosis of AT/RT and briefly analyzed its genomic features, which might offer a valuable tool to address existing clinical challenges.

p53 suppresses the inflammatory response following respiratory syncytial virus infection by inhibiting TLR2.

-Respiratory syncytial virus (RSV) is a pivotal virus leading to acute lower respiratory tract infections in children under 5 years old. This study aimed to explore the correlation between p53 and Toll-like receptors (TLRs) post RSV infection. p53 levels exhibited a substantial decrease in nasopharyngeal aspirates (NPAs) from infants with RSV infection compared to control group. Manipulating p53 expression had no significant impact on RSV replication or interferon signaling pathway. Suppression of p53 expression led to heightened inflammation following RSV infection in A549 cells or airways of BALB/c mice. while stabilizing p53 expression using Nutlin-3a mitigated the inflammatory response in A549 cells. Additionally, Inhibiting p53 expression significantly increased Toll-like receptor 2 (TLR2) expression in RSV-infected epithelial cells and BALB/c mice. Furthermore, the TLR2 inhibitor, C29, effectively reduced inflammation mediated by p53 in A549 cells. Collectively, our results indicate that p53 modulates the inflammatory response after RSV infection through TLR2.

MXene-mediated reconfiguration induces robust nickel-iron catalysts for industrial-grade water oxidation.

Nickel-iron oxy/hydroxides (NiFeOxHy) emerge as an attractive type of electrocatalysts for alkaline water oxidation reaction (WOR), but which encounter a huge challenge in stability, especially at industrial-grade large current density due to uncontrollable Fe leakage. Here, we tailor the Fe coordination by a MXene-mediated reconfiguration strategy for the resultant NiFeOxHy catalyst to alleviate Fe leakage and thus reinforce the WOR stability. The introduction of ultrafine MXene with surface dangling bonds in the electrochemical reconfiguration over Ni-Fe Prussian blue analogue induces the covalent hybridization of NiFeOxHy/MXene, which not only accelerates WOR kinetics but also improves Fe oxidation resistance against segregation. As a result, the NiFeOxHy coupled with MXene exhibits an extraordinary durability at ampere-level current density over 1,000 h for alkaline WOR with an ultralow overpotential of only 307 mV. This work provides a broad avenue and mechanistic insights for the development of nickel-iron catalysts toward industrial applications.

ATF4 in cellular stress, ferroptosis, and cancer.

Activating transcription factor 4 (ATF4), a member of the ATF/cAMP response element-binding (CREB) family, plays a critical role as a stress-induced transcription factor. It orchestrates cellular responses, particularly in the management of endoplasmic reticulum stress, amino acid deprivation, and oxidative challenges. ATF4's primary function lies in regulating gene expression to ensure cell survival during stressful conditions. However, when considering its involvement in ferroptosis, characterized by severe lipid peroxidation and pronounced endoplasmic reticulum stress, the ATF4 pathway can either inhibit or promote ferroptosis. This intricate relationship underscores the complexity of cellular responses to varying stress levels. Understanding the connections between ATF4, ferroptosis, and endoplasmic reticulum stress holds promise for innovative cancer therapies, especially in addressing apoptosis-resistant cells. In this review, we provide an overview of ATF4, including its structure, modifications, and functions, and delve into its dual role in both ferroptosis and cancer.

Interplay of Ferroptosis and Cuproptosis in Cancer: Dissecting Metal-Driven Mechanisms for Therapeutic Potentials.

Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings.

Targeting paraptosis in cancer: opportunities and challenges.

Cell death can be classified into two primary categories: accidental cell death and regulated cell death (RCD). Within RCD, there are distinct apoptotic and non-apoptotic cell death pathways. Among the various forms of non-apoptotic RCD, paraptosis stands out as a unique mechanism characterized by distinct morphological changes within cells. These alterations encompass cytoplasmic vacuolization, organelle swelling, notably in the endoplasmic reticulum and mitochondria, and the absence of typical apoptotic features, such as cell shrinkage and DNA fragmentation. Biochemically, paraptosis distinguishes itself by its independence from caspases, which are conventionally associated with apoptotic death. This intriguing cell death pathway can be initiated by various cellular stressors, including oxidative stress, protein misfolding, and specific chemical compounds. Dysregulated paraptosis plays a pivotal role in several critical cancer-related processes, such as autophagic degradation, drug resistance, and angiogenesis. This review provides a comprehensive overview of recent advancements in our understanding of the mechanisms and regulation of paraptosis. Additionally, it delves into the potential of paraptosis-related compounds for targeted cancer treatment, with the aim of enhancing treatment efficacy while minimizing harm to healthy cells.