Our study aimed to elucidate the potential necroptotic&mitophagy-related key genes in colorectal cancer (COAD) by bioinformatics analysis and identify their prognostic value in COAD.

Firstly, we integrated the cancer genome atlas (TCGA) and gene expression omnibus (GEO) datasets to identify necroptosis & mitophagy-related differentially expressed genes (N&MRDEGs) in COAD using "TCGAbiolinks" and "GEOquery" packages. Secondly, the obtained data were used for differential expression analysis using the "limma" package, and further functional enrichment analysis using the "clusterProfiler" package. Then, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were utilized to explore pathway associations of the N&MRDEGs. Thirdly, the predictive model was developed utilizing LASSO (Least absolute shrinkage and selection regression) regression implemented through the "glmnet" package and validated via Kaplan-Meier analysis. Finally, we validated the function of the key genes by receiver operating characteristic (ROC) curve analysis, multivariate cox proportional hazards model and COAD cell lines.

There is a strong association between the 4 key genes (UCHL1, HSPA1A, MAPK8, and PLEC) of COAD and the necroptotic&mitophagy, which were found to be lowly mRNA level in COAD cell lines. Among them, PLEC exhibited a pronounced contribution to the utility of the model in the TCGA database and UCHL1 has excellent diagnostic potential with an area under the curve (AUC) greater than 0.9.

The perspective of bioinformatics analysis provides robust evidence suggested that UCHL1, HSPA1A, MAPK8, and PLEC genes are the prognostic biomarkers of COAD, the predictive model established herein provides a novel tool for risk stratification in clinical practice and serves as a foundation for further investigation into its underlying molecular mechanisms.

Phototherapy has emerged as a promising modality in cancer treatment, garnering considerable attention for its minimal side effects, exceptional spatial selectivity, and optimal preservation of normal tissue function. This innovative approach primarily encompasses three distinct paradigms: Photodynamic Therapy (PDT), Photothermal Therapy (PTT), and Photoimmunotherapy (PIT). Each of these modalities exerts its antitumor effects through unique mechanisms-specifically, the generation of reactive oxygen species (ROS), heat, and immune responses, respectively. However, significant challenges impede the advancement and clinical application of phototherapy. These include inadequate ROS production rates, subpar photothermal conversion efficiency, difficulties in tumor targeting, and unfavorable physicochemical properties inherent to traditional phototherapeutic agents (PTs). Additionally, the hypoxic microenvironment typical of tumors complicates therapeutic efficacy due to limited agent penetration in deep-seated lesions. To address these limitations, ongoing research is fervently exploring innovative solutions. The unique advantages offered by nano-PTs and nanocarrier systems aim to enhance traditional approaches' effectiveness. Strategies such as generating oxygen in situ within tumors or inhibiting mitochondrial respiration while targeting the HIF-1α pathway may alleviate tumor hypoxia. Moreover, utilizing self-luminescent materials, near-infrared excitation sources, non-photoactivated sensitizers, and wireless light delivery systems can improve light penetration. Furthermore, integrating immunoadjuvants and modulating immunosuppressive cell populations while deploying immune checkpoint inhibitors holds promise for enhancing immunogenic cell death through PIT. This review seeks to elucidate the fundamental principles and biological implications of phototherapy while discussing dominant mechanisms and advanced strategies designed to overcome existing challenges-ultimately illuminating pathways for future research aimed at amplifying this intervention's therapeutic efficacy.

Acute coronary events show a diurnal rhythm, and atherosclerotic plaque vulnerability, as a histomorphological characteristic of major adverse cardiovascular events, is a key target for intervention. Although oscillating microRNAs reduce plaque stability by facilitating macrophage apoptosis in lesions, whether rhythmic long non-coding RNA (lncRNA) can regulate diurnal oscillations in plaque stability and the potential underlying mechanism remain unclear. In this study, we examined whether rhythmic lncRNAs are involved in the pathogenesis and progression of atherosclerosis and detected a novel circadian lncRNA-AK023617, which is positively correlated with the peak occurrence of major adverse cardiovascular events. Transfection of short interfering RNA specific to lnc-AK023617 into THP-1 cells dampened the oscillation of immunity-related GTPase family M protein 1 (Irgm1), which is negatively related to plaque stability. In ApoE-/- mice fed a high-fat diet for 12 weeks, diurnal variations in lncAK023617 were consistent with the proportions of necroptotic cells in atherosclerotic plaques. In addition, reduced expression of lncAK023617 inhibited P-RIP3 and P-MLKL in THP-1 cells. Mechanistically, lncAK023617 interacted with the core molecular clock Bmal1 and promoted nuclear translocation of Bmal1, which could directly bind to the E-BOX elements in the Irgm1 promoter. Thus, oscillating lncAK023617 in macrophages can affect plaque stability by regulating necroptosis, which regulates circadian expression of the target gene Irgm1 by increasing the transcriptional activity of Bmal1, ultimately determining the diurnal oscillations in plaque stability. Therefore, lncAK023617 may serve as a specific target to ameliorate atherosclerotic plaque vulnerability.

Central nervous system (CNS) injury causes severe organ damage due to both damage resulting from the injury and subsequent cell death. However, there are currently no effective treatments for countering the irreversible loss of cell function. Parthanatos is a poly (ADP-ribose) polymerase 1 (PARP-1)-dependent form of programmed cell death that is partly responsible for neural cell death. Consequently, the mechanism by which parthanatos promotes CNS injury has attracted significant scientific interest.

Our review aims to summarize the potential role of parthanatos in CNS injury and its molecular and pathophysiological mechanisms. Understanding the role of parthanatos and related molecules in CNS injury is crucial for developing effective treatment strategies and identifying important directions for future in-depth research.

Parthanatos (from Thanatos, the personification of death according to Greek mythology) is a type of programmed cell death that is initiated by the overactivation of PARP-1. This process triggers a cascade of reactions, including the accumulation of poly(ADP-ribose) (PAR), the nuclear translocation of apoptosis-inducing factor (AIF) after its release from mitochondria, and subsequent massive DNA fragmentation caused by migration inhibitory factor (MIF) forming a complex with AIF. Secondary molecular mechanisms, such as excitotoxicity and oxidative stress-induced overactivation of PARP-1, significantly exacerbate neuronal damage following initial mechanical injury to the CNS. Furthermore, parthanatos is not only associated with neuronal damage but also interacts with various other types of cell death. This review focuses on the latest research concerning the parthanatos cell death pathway, particularly considering its regulatory mechanisms and functions in CNS damage. We highlight the associations between parthanatos and different cell types involved in CNS damage and discuss potential therapeutic agents targeting the parthanatos pathway.

Cancer is characterized by unregulated cell proliferation, evasion of apoptosis, and a propensity for metastasis, making it a leading cause of morbidity and mortality globally. Major challenges in cancer treatment include drug resistance and tumor heterogeneity, which hinder the clinical efficacy of existing therapies. To enhance treatment outcomes, it is essential to integrate emerging biological insights and technological advancements with conventional therapeutic strategies. Recent research has identified various forms of cell death, which can be classified as either regulated or unregulated. Regulated cell death involves specific biochemical and signaling pathways, while unregulated cell death occurs passively and uncontrollably. Apoptosis, the most extensively studied form of regulated cell death, is primarily mediated by the activation of caspase proteases. Nevertheless, the resistance of many tumors to apoptotic pathways has shifted focus towards non-apoptotic forms of cell death, such as ferroptosis. Ferroptosis is an iron-dependent form of regulated necrosis characterized by extensive membrane damage resulting from lipid peroxidation. Numerous preclinical studies have demonstrated that inducing ferroptosis can significantly reduce tumor growth across a variety of cancer types. For instance, in a study involving breast cancer models, the use of ferroptosis inducers such as erastin and RSL3 led to a marked decrease in tumor volume and weight. This review aims to explore the potential of ferroptosis as a novel therapeutic strategy in cancer treatment.

The core syndrome among NBIA disorders is pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder caused by mutations in the PANK2 gene. There is no therapy for PKAN; only symptomatic treatment is available. Our work aimed to identify the mechanisms induced by biochemical disturbances in the cell cycle and identify potential pharmacological targets to improve patient quality of life. Mass spectrometry (MS) (metals) and NMR spectroscopy (hydrophilic and hydrophobic compounds) were used for profile analyses of the sera of 12 PKAN patients and 12 controls to study the compounds involved in PKAN pathomechanisms. We performed ANOVA and multivariate analysis using orthogonal partial least squares discriminant analysis. We have shown for the first time that patients have 100-500-fold greater serum citrate levels than controls do, which may contribute to Fe transport and ferroptosis. Ferroptosis may be indicated by disturbances in the levels of many metals, oxidative stress, disturbances in energy production and neurotransmission or dysfunction of biological membranes. Our findings suggest that ferroptosis could be a primary cause of cell death in PKAN patients. This could be indicated by serum metabolomics.

Chemical investigation of a MeOH extract of the Red Sea sponge Stylissa carteri, offered a new bromopyrrole alkaloid named stylisinone (1) along with other eight pyrrole alkaloids. The structures were established by comprehensive spectroscopic analyses of NMR and MS, as well as by comparison with the literature. The in vitro anticancer activity of the isolated alkaloids was evaluated against human cancer cell lines, HepG2, MCF-7, LS513, A549, and THP1, and BM as normal mice cells. The results showed that stylisinone had the highest cytotoxicity against the A549 cell line, with IC50 values at 24.08 µM, respectively. The new metabolite stylisinone caused strong cell cycle arrest at sub G1 and G2/M (22.43-fold and 2.28-fold, respectively), indicating its potential as an antitumor agent. Furthermore, stylisinone showed a marked increase in Annexin V-FITC necrotic cells (from 1.23 to 21.38%), making this molecule an attractive candidate for further mechanism of action studies.

Kidney stones represent a highly prevalent urological disorder worldwide, with high incidence and recurrence rates. Calcium oxalate (CaOx) crystal-induced kidney injury serves as the foundational mechanism for the formation and progression of CaOx stones. Regulated cell death (RCD) such as ferroptosis, necroptosis, and pyroptosis are essential in the pathophysiological process of kidney injury. Ferroptosis, a newly discovered RCD, is characterized by its reliance on iron-mediated lipid peroxidation. Necroptosis, a widely studied programmed necrosis, initiates with a necrotic phenotype that resembles apoptosis in appearance. Pyroptosis, a type of RCD that involves the gasdermin protein, is accompanied by inflammation and immune response. In recent years, increasing amounts of evidence has demonstrated that ferroptosis, necroptosis, and pyroptosis are significant pathophysiological processes involved in CaOx crystal-induced kidney injury. Herein, we summed up the roles of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury. Furthermore, we delved into the curative potential of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury.

Iron is essential in various physiological processes, but its accumulation leads to oxidative stress and cell damage, thus iron homeostasis has to be tightly regulated. Ferroptosis is an iron-dependent non-apoptotic regulated cell death characterized by iron overload and reactive oxygen species accumulation. Mitochondria are organelles playing a crucial role in iron metabolism and involved in ferroptosis. MitoNEET, a protein of mitochondrial outer membrane, is a key element in this process. Ferroptosis, altering iron levels in several metabolically active organs, is linked to several non-communicable diseases. For example, iron overload in the liver leads to hepatic fibrosis and cirrhosis, accelerating non-alcholic fatty liver diseases progression, in the muscle cells contributes to oxidative damage leading to sarcopenia, and in the brain is associated to neurodegeneration. The aim of this review is to investigate the intricate balance of iron regulation focusing on the role of mitochondria and oxidative stress, and analyzing the ferroptosis implications in health and disease.

Chemotherapy for cancer frequently uses platinum-based medications, including oxaliplatin, carboplatin, and cisplatin; however, due to their high systemic toxicity, lack of selectivity, drug resistance, and other side effects, platinum-based medications have very limited clinical application. As a first-line medication in antitumor therapy, oxaliplatin must be administered to minimize side effects while achieving anticancer objectives. A new CDC7 inhibitor called XL413 has demonstrated promising antitumor therapeutic effects in a variety of malignant tumors and may have anticancer properties. This offers a fresh viewpoint on how to lessen oxaliplatin resistance and, specifically, increase the potency of already prescribed anticancer therapies. In this paper, the current developments in anticancer therapy are discussed, along with the many mechanisms of oxaliplatin's antitumor effects, clinical treatment challenges, and related approaches. We conducted more research on oxaliplatin resistance that arose during chemotherapy and searched for ways to lessen it in order to enhance its chemotherapeutic performance. Ultimately, we studied how distinct resistance routes relate to one another. Meanwhile, XL413, a novel CDC7 inhibitor, offers a perspective on the possibilities for developing treatment approaches for this innovation point. The search terms "Oxaliplatin, XL413, drug resistance, cancer treatment," etc., were applied in the X-MOL and PubMed databases for this review's literature search. Boolean logic was then employed to maximize the search approach. These databases can offer thorough research data and cover a broad range of biological publications. Excluded publications were works of low relevance, duplicates, or those with insufficient information. The mechanism of oxaliplatin's anticancer effect, oxaliplatin resistance and its amelioration, and the role of XL413 in oxaliplatin treatment were the main topics of the 140 publications that were ultimately included for analysis.

Lytic cell death including necroptosis and pyroptosis is induced by mixed lineage kinase domain-like protein (MLKL) phosphorylation and inflammatory caspase specific cleavage Gasdermins in higher mammals, respectively. In this study, we identified a novel MLKL homolog containing a tetrapeptide recognition motif (14-LVAD-17) of inflammatory caspase from Apostichopus japonicus,which was absent of Gasdermins member by genome screening. Functional analysis revealed that AjMLKL was involved in the regulation of Vibrio splendidus AJ01 infection induced lytic coelomocyte death in a cleavage-dependent manner, but not through RIPK3-dependent phosphorylation as mammals. Mechanistically, the activated form of cysteine-aspartic specific proteases-1 (AjCASP-1) bound to the tetrapeptide site of AjMLKL and cleaved it at Asp17. Cleaved AjMLKL18-491 displayed higher binding affinities towards phosphatidylinositol phosphate and cardiolipin compared to those of un-cleaved form. In addition, cleaved AjMLKL18-491 exerted stronger ability in disrupting the membrane integrity of liposome. More importantly, AjMLKL18-491 caused a large non-selective ionic coelomocyte pore and could directly kill the invasive AJ01. Moreover, activation of inflammatory AjCASP-1 was further found to be dependent on forming an inflammasome-like complex via CASc domain of AjCASP-1 and the N-terminal Ig domains of internalized AjNLRC4. All our results proved first evidence that lytic cell death was activated through MLKL cleavage, not MLKL phosphorylation in echinoderm, which offered insights into the functional, evolutionary mechanisms of lytic cell death in invertebrates.

Hydrogen peroxide (H2O2) is a ubiquitous signal regulating many biological processes, including innate immunity, in all eukaryotes. However, it remains largely unknown that how transcription factors directly sense H2O2 in eukaryotes. Here, we report that rice basic/helix-loop-helix transcription factor bHLH25 directly senses H2O2 to confer resistance to multiple diseases caused by fungi or bacteria. Upon pathogen attack, rice plants increase the production of H2O2, which directly oxidizes bHLH25 at methionine 256 in the nucleus. Oxidized bHLH25 represses miR397b expression to activate lignin biosynthesis for plant cell wall reinforcement, preventing pathogens from penetrating plant cells. Lignin biosynthesis consumes H2O2 causing accumulation of non-oxidized bHLH25. Non-oxidized bHLH25 switches to promote the expression of Copalyl Diphosphate Synthase 2 (CPS2), which increases phytoalexin biosynthesis to inhibit expansion of pathogens that escape into plants. This oxidization/non-oxidation status change of bHLH25 allows plants to maintain H2O2, lignin and phytoalexin at optimized levels to effectively fight against pathogens and prevents these three molecules from over-accumulation that harms plants. Thus, our discovery reveals a novel mechanism by which a single protein promotes two independent defense pathways against pathogens. Importantly, the bHLH25 orthologues from available plant genomes all contain a conserved M256-like methionine suggesting the broad existence of this mechanism in the plant kingdom. Moreover, this Met-oxidation mechanism may also be employed by other eukaryotic transcription factors to sense H2O2 to change functions.

Mixed lineage kinase domain-like protein (MLKL) is a key component of necroptosis. Here, serum MLKL levels were measured with the intent to assess its prognostic significance in acute intracerebral hemorrhage (ICH).

A collective of 161 patients with acute primary supratentorial ICH and 73 controls were enlisted in this multicenter prospective cohort study. Serum MLKL levels were measured at admission in all patients, at study entry in all controls, and on post-ICH days 1, 3, 5, 7, 10, and 15 in 73 of all patients. Multivariate analyses were adopted to assess relationships between serum MLKL levels, severity, early neurological deterioration (END), poststroke 6-month modified Rankin Scale (mRS) scores, and poor prognosis (mRS scores of 3-6).

Patients, relative to controls, had significantly promoted serum MLKL levels from admission until Day 15, with the peaking value at Day 3 (p < 0.001). Admission serum MLKL levels were independently correlated with National Institutes of Health Stroke Scale (NIHSS) scores (beta, 0.133; 95% confidence interval (CI), 0.088-0.178; p = 0.011), hematoma volume (beta, 0.051; 95%CI, 0.037-0.064; p = 0.001), and 6-month mRS scores (beta, 0.707; 95%CI, 0.487-0.927; p = 0.023), as well as independently predicted END (odds ratio, 1.902; 95%CI, 1.229-2.945; p = 0.014) and poor prognosis (odds ratio, 2.286; 95%CI, 1.324-3.946; p = 0.038). Admission serum MLKL levels were linearly connected to risks of poor prognosis (p > 0.05) and END (p > 0.05), had no interactions with age, gender, hypertension, and so forth (all p > 0.05), and possessed similar areas under the receiver operating characteristic curve to NIHSS scores and hematoma volume (all p > 0.05). The models integrating serum MLKL levels, NIHSS scores, and hematoma volume were graphically represented by nomogram and predicted END and poor prognosis with a good consistency under the calibration curve.

Serum MLKL levels are markedly increased shortly following ICH, and may accurately mirror disease severity, and efficaciously anticipate END and six-month bad prognosis of patients, strengthening serum MLKL as a prognostic biomarker of good prospect in ICH.

As an important component of the cell wall of Gram-negative bacteria, lipopolysaccharide (LPS) is an important inducer of inflammation in humans. Smilax china L. is known for its diverse bioactive functions, particularly its anti-inflammatory effects.

This study aimed to investigate the bioactive function of Smilax china L. polyphenols (SCLP) on LPS-induced inflammation.

Inflammation in RAW264.7 macrophages and mice were induced using LPS. The cytotoxicity of SCLP was investigated by MTT assay. Inflammatory factors were detected by ELISA and RT-PCR. The expression of NF-κB pathway-related proteins was analyzed by Western Blotting.

The results demonstrated that SCLP significantly reduced the levels of pro-inflammatory factors (TNF-α, IL-1β, and IL-6) and inhibited M1 polarization of macrophages in both RAW264.7 macrophages and mice (p < 0.05). Western Blotting analysis revealed that the levels of NF-κB signaling pathway-associated proteins (p-p65, p-IKB, p-IKK) were significantly reduced (p < 0.05). Notably, SCLP significantly downregulated the expression of pro-apoptotic proteins, while upregulating the expression of anti-apoptotic proteins in RAW264.7 macrophages (p < 0.05). Additionally, the levels of antioxidant enzymes were enhanced in mice, suggesting a potential reduction in the inflammatory response.

These findings indicated that SCLP might inhibit LPS-induced M1 polarization through the NF-κB signaling pathway, thereby reducing inflammation. Consequently, SCLP might serve as a promising bioactive substance for preventing inflammation-related injury.

Ferroptosis, an iron-dependent form of regulatory cell death, has garnered significant interest as a therapeutic target in cancer treatment due to its distinct characteristics, including lipid peroxide generation and redox imbalance. However, its clinical application in oncology is currently limited by issues such as suboptimal efficacy and potential off-target effects. The advent of nanotechnology has provided a new way for overcoming these challenges through the development of activatable magnetic nanoparticles (MNPs). These innovative MNPs are designed to improve the specificity and efficacy of ferroptosis induction. This Review delves into the chemical and biological principles guiding the design of MNPs for ferroptosis-based cancer therapies and imaging-guided therapies. It discusses the regulatory mechanisms and biological attributes of ferroptosis, the chemical composition of MNPs, their mechanism of action as ferroptosis inducers, and their integration with advanced imaging techniques for therapeutic monitoring. Additionally, we examine the convergence of ferroptosis with other therapeutic strategies, including chemodynamic therapy, photothermal therapy, photodynamic therapy, sonodynamic therapy, and immunotherapy, within the context of nanomedicine strategies utilizing MNPs. This Review highlights the potential of these multifunctional MNPs to surpass the limitations of conventional treatments, envisioning a future of drug-resistance-free, precision diagnostics and ferroptosis-based therapies for treating recalcitrant cancers.

NINJ1 was initially recognized for its role in nerve regeneration and cellular adhesion. Subsequent studies have uncovered its participation in cancer progression, where NINJ1 regulates critical steps in tumor metastasis, such as cell migration and invasion. More recently, NINJ1 has emerged as a multifunctional protein mediating plasma membrane rupture (PMR) in several lytic cell death processes, including apoptosis, necroptosis, and pyroptosis. However, its role in ferroptosis-an iron-dependent form of lytic cell death characterized by lipid peroxidation-remained unclear until 2024. Ferroptosis is a tumor suppression mechanism that may be particularly relevant to detached and metastatic cancer cells. This review explores the role of NINJ1 in tumor invasion and metastasis, focusing on its regulation of ferroptosis via a non-canonical mechanism distinct from other cell deaths. We discuss the process of ferroptosis and its implications for cancer invasion and metastasis. Furthermore, we review recent studies highlighting the diverse roles of NINJ1 in ferroptosis regulation, including its canonical function in PMR and its non-canonical function of modulating intracellular levels of glutathione (GSH) and coenzyme A (CoA) via interaction with xCT anti-porter. Given that ferroptosis has been associated with tumor suppression, metastasis, the elimination of treatment-resistant cancer cells, and tumor dormancy, NINJ1's modulation of ferroptosis presents a promising therapeutic target for inhibiting metastasis. Understanding the dual role of NINJ1 in promoting or restraining ferroptosis depending on cellular context could open avenues for novel anti-cancer strategies to enhance ferroptotic vulnerability in metastatic tumors.

Ten years after the description of the first cohorts of patients with adenosine deaminase (ADA2) deficiency (DADA2), the pathomechanisms underlying the disease on a cellular level remain poorly understood. With the establishment of the lysosomal localization of the ADA2 protein and its involvement in nucleic acid sensing, the pathophysiologic focus has shifted to the inside of the cell. At the same time, extracellular (serum) ADA2 enzyme activity continues to be the diagnostic reference standard in patients with suspected DADA2. The diverse clinical phenotype and weak genotype-phenotype correlations further complicate the identification of shared cellular mechanisms that cause inflammation, immunodeficiency, and bone marrow failure in the absence of functional ADA2. This review inspects the characteristics of the ADA2 protein and its proposed function. The latter is discussed in the context of possible mechanisms driving the clinical phenotype in patients lacking functional ADA2. We discuss established processes and introduce unexplored pathways in the pathogenesis of DADA2.

In hepatocellular carcinoma (HCC) individuals, the influence of numerous variables on the HCC prognosis has gained widespread recognition. Nevertheless, there remains a need for further elucidation regarding the underlying mechanism of PANoptosis-related genes (PRGs) on HCC. A consensus clustering approach, based on the TCGA-LIHC data, was used to identify specific subtypes linked to PANoptosis in this study. Next, a signature consisting of predictive differentially expressed genes for these subtypes was established using a least absolute shrinkage and selection operator (LASSO) regression analysis. Additionally, the reliability of the signature was confirmed through verification investigations using the data from the ICGC database and TCGA-LIHC. In the end, we developed a nomogram to enhance the clinical effectiveness of our prediction tool. PRG signature in this study has been highly related to the prognosis of individuals diagnosed with HCC, which was established with six genes. Also, this signature and clinicopathological features were put together to create a nomogram. Interestingly, the forecasting efficiency of this combination approach is better than other prediction models in the reported literature. In addition, an examination of the immunological surroundings indicates that the group with low risk exhibited elevated ESTIMATE score, ImmuneScores, and StromalScores. More, significant differences in infiltrating immune cells and the expression levels of immune-related genes were found between the two groups. In HCC patients, the PRG signature exhibits potential as a biomarker, offering a significant point of reference for tailoring individual therapy.

Human and animal health rely on balancing cell division and cell death to maintain normal homeostasis. This process is accomplished by regulated cell death (RCD), whose imbalance can lead to disease. Currently, the most frequently used method for analyzing RCD is fluorescence microscopy. This method has limitations and potential side effects due to the presence of fluorescent labels. Furthermore, fluorescence often lacks specificity and may have side effects. In the quest to overcome such difficulties, label-free approaches have come into focus.Here, Raman microscopy in combination with machine learning is used to investigate RCDs, where biochemical molecular "fingerprints" are investigated with a focus on the vibrations of atoms in molecules. Three different and unique RCD types with different genetic and biochemical machinery, namely, ferroptosis is studied in comparison with apoptosis, and necroptosis in the murine fibroblast line L929sAhFas. Interestingly, during ferroptosis, a decrease in the wavenumber at 939 cm-1 was observed, which is associated with a potential reduction in the expression of collagen - a compound essential in multiple diseases. Data analysis was performed by machine learning (ML), here SVMs, where the model utilizing the spectra directly into a support vector machine (SVM) outperforms other SVM strategies correctly predicting 73% of all spectra. Other methods: PCA-SVM (principal component analysis-SVM), peak fitting-AUC-SVM (area under the curve) and peak fitting-spectral reconstruction-SVM rendered prediction accuracies of ~52%, ~43%, and 61%, respectively. Peak fitting has the additional benefit of enabling the biological interpretation of Raman scattering peaks by using the area under the curve, although at a loss of general accuracy. The potential of Raman microscopy in biology, in combination with machine learning pipelines, can be applied to a broader field of cell biology, not limited to regulated cell death.

The phenomenon of cell death has garnered significant scientific attention in recent years, emerging as a pivotal area of research. Recently, novel modalities of cellular death and the intricate interplay between them have been unveiled, offering insights into the pathogenesis of various diseases. This comprehensive review delves into the intricate molecular mechanisms, inducers, and inhibitors of the underlying prevalent forms of cell death, including apoptosis, autophagy, ferroptosis, necroptosis, mitophagy, and pyroptosis. Moreover, it elucidates the crosstalk and interconnection among the key pathways or molecular entities associated with these pathways, thereby paving the way for the identification of novel therapeutic targets, disease management strategies, and drug repurposing.

Osteoarthritis (OA) is a common degenerative joint disease characterized by the progressive degradation of articular cartilage, synovial inflammation, and subchondral bone remodeling. This review explores the interplay between aging, PANoptosis, and inflammation in OA progression. Age-related cellular and immune dysfunctions, including cellular senescence, senescence-associated secretory phenotypes (SASPs), and immunosenescence, significantly contribute to joint degeneration. In OA, dysregulated apoptosis, necroptosis, and pyroptosis, particularly in chondrocytes, exacerbate cartilage damage. Apoptosis, mediated by the JNK pathway, reduces chondrocyte density, while necroptosis and pyroptosis, involving RIPK-1/RIPK-3 and the NLRP3 inflammasome, respectively, amplify inflammation and cartilage destruction. Inflammatory cytokines and damage-associated molecular patterns (DAMPs) further enhance these PANoptotic pathways. Current therapeutic strategies primarily focus on anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, with growing interest in anti-senescence drugs targeting cellular senescence and SASP. Additionally, exploring PANoptosis mechanisms offers potential for innovative OA treatments.

Intracellular metal ions play essential roles in multiple physiological processes, including catalytic action, diverse cellular processes, intracellular signaling, and electron transfer. It is crucial to maintain intracellular metal ion homeostasis which is achieved by the subtle balance of storage and release of metal ions intracellularly along with the influx and efflux of metal ions at the interface of the cell membrane. Dysregulation of intracellular metal ions has been identified as a key mechanism in triggering programmed cell death (PCD). Despite the importance of metal ions in initiating PCD, the molecular mechanisms of intracellular metal ions within these processes are infrequently discussed. An in-depth understanding and review of the role of metal ions in triggering PCD may better uncover novel tools for cancer diagnosis and therapy. Specifically, the essential roles of calcium (Ca2+), iron (Fe2+/3+), copper (Cu+/2+), and zinc (Zn2+) ions in triggering PCD are primarily explored in this review, and other ions like manganese (Mn2+/3+/4+), cobalt (Co2+/3+) and magnesium ions (Mg2+) are briefly discussed. Further, this review elaborates on the underlying chemical mechanisms and summarizes these metal ions triggering PCD in cancer therapy. This review bridges chemistry, immunology, and biology to foster the rational regulation of metal ions to induce PCD for cancer therapy.

PANoptosis is an emerging form of regulated cell death (RCD) characterized by simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling that not only participates in pathologies of inflammatory diseases but also has a critical role against pathogenic infections. Targeting PANoptosis represents a promising therapeutic strategy for related inflammatory diseases, but identification of inhibitors for PANoptosis remains an unmet demand. Baicalin () is an active flavonoid isolated from Scutellaria baicalensis Georgi (Huangqin), a traditional Chinese medicinal herb used for heat-clearing and detoxifying. Numerous studies suggest that baicalin possesses inhibitory activities on various forms of RCD including apoptosis/secondary necrosis, pyroptosis, and necroptosis, thereby mitigating inflammatory responses. In this study we investigated the effects of baicalin on PANoptosis in macrophage cellular models. Primary macrophages (BMDMs) or J774A.1 macrophage cells were treated with 5Z-7-oxozeaenol (OXO, an inhibitor for TAK1) in combination with TNF-α or LPS. We showed that OXO plus TNF-α or LPS induced robust lytic cell death, which was dose-dependently inhibited by baicalin (50-200 μM). We demonstrated that PANoptosis induction was accompanied by overt mitochondrial injury, mitochondrial DNA (mtDNA) release and Z-DNA formation. Z-DNA was formed from cytosolic oxidized mtDNA. Both oxidized mtDNA and mitochondrial Z-DNA puncta were co-localized with the PANoptosome (including ZBP1, RIPK3, ASC, and caspase-8), a platform for mediating PANoptosis. Intriguingly, baicalin not only prevented mitochondrial injury but also blocked mtDNA release, Z-DNA formation and PANoptosome assembly. Knockdown of ZBP1 markedly decreased PANoptotic cell death. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), administration of baicalin (200 mg/kg, i.g., for 4 times) significantly mitigated lung and liver injury and reduced levels of serum TNF-α and IFN-γ, concomitant with decreased levels of PANoptosis hallmarks in these organs. Baicalin also abrogated the hallmarks of PANoptosis in liver-resident macrophages (Kupffer cells) in HLH mice. Collectively, our results demonstrate that baicalin inhibits PANoptosis in macrophages by blocking mitochondrial Z-DNA formation and ZBP1-PANoptosome assembly, thus conferring protection against inflammatory diseases. PANoptosis is a form of regulated cell death displaying simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling. This study shows that induction of PANoptosis is linked to mitochondrial dysfunction and mitochondrial Z-DNA formation. Baicalin inhibits PANoptosis in macrophages in vitro via blocking mitochondrial dysfunction and the mitochondrial Z-DNA formation and thereby impeding the assembly of ZBP1-associated PANoptosome. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), baicalin inhibits the activation of PANoptotic signaling in liver-resident macrophages (Kupffer cells) in vivo, thus mitigating systemic inflammation and multiple organ injury in mice.

Normal brain functioning relies on high aerobic energy production provided by mitochondria. Failure to supply a sufficient amount of energy, seen in different brain disorders, including autism spectrum disorder (ASD), may have a significant negative impact on brain development and support of different brain functions. Mitochondrial dysfunction, manifested in the abnormal activities of the electron transport chain and impaired energy metabolism, greatly contributes to ASD. The aberrant functioning of this organelle is of such high importance that ASD has been proposed as a mitochondrial disease. It should be noted that aerobic energy production is not the only function of the mitochondria. In particular, these organelles are involved in the regulation of Ca2+ homeostasis, different mechanisms of programmed cell death, autophagy, and reactive oxygen and nitrogen species (ROS and RNS) production. Several syndromes originated from mitochondria-related mutations display ASD phenotype. Abnormalities in Ca2+ handling and ATP production in the brain mitochondria affect synaptic transmission, plasticity, and synaptic development, contributing to ASD. ROS and Ca2+ regulate the activity of the mitochondrial permeability transition pore (mPTP). The prolonged opening of this pore affects the redox state of the mitochondria, impairs oxidative phosphorylation, and activates apoptosis, ultimately leading to cell death. A dysregulation between the enhanced mitochondria-related processes of apoptosis and the inhibited autophagy leads to the accumulation of toxic products in the brains of individuals with ASD. Although many mitochondria-related mechanisms still have to be investigated, and whether they are the cause or consequence of this disorder is still unknown, the accumulating data show that the breakdown of any of the mitochondrial functions may contribute to abnormal brain development leading to ASD. In this review, we discuss the multifaceted role of mitochondria in ASD from the various aspects of neuroscience.

Osteosarcoma, a highly aggressive malignancy with a generally poor prognosis, is characterized by tumor cells' ability to evade immune responses and resist treatment. The nuclear transcription factor NF-κB signaling pathway is crucial in regulating inflammatory and immune reactions. It occupies a central position in the development of the osteosarcoma tumor microenvironment. This research aimed to explore how NF-κB influences the recruitment and polarization of tumor-associated macrophages and myeloid-derived suppressor cells, both of which contribute to immunosuppression. Furthermore, NF-κB facilitates immune surveillance evasion in osteosarcoma cells by altering the expression of immune checkpoint molecules, such as PD-L1. It also enhances tumor cell resistance to chemotherapy and radiotherapy by activating anti-apoptotic signaling pathways and exacerbating treatment-induced inflammation. Potential therapeutic approaches include using NF-κB inhibitors, possibly in combination with immune checkpoint inhibitors, to overcome tumor cell resistance mechanisms and reshape antitumor immune responses. A thorough examination of NF-κB's role in osteosarcoma development is expected to yield novel clinical treatment strategies, and significantly improve patient prognosis by targeting this key signaling pathway.

Nasopharyngeal carcinoma (NPC), one of the most common malignancies of the head and neck, is characterised by a complex pathogenesis and an unfavourable prognosis. Recently, disulfidoptosis, a novel form of cell death, has been proposed. Several studies in recent years have extensively investigated the function of the disulfidoptosis-related SLC7A11 gene in cancer, but the role of its partner protein, SLC3A2, remains unknown unclear in NPC.

GEO database analysis confirmed SLC3A2's prognostic impact on nasopharyngeal carcinoma. ROC, Kaplan-Meier analyses, and stage-specific expression studies showed a strong correlation with poor HNSC prognosis. GO and KEGG analyses pinpointed relevant signaling pathways. In vitro, SLC3A2's influence on cell proliferation, migration, and invasion was evaluated through CCK8, wound healing, colony formation, transwell assays, and cell cycle analysis.

In this study, we identified the high expression of SLC3A2 in NPC and head and neck squamous cell carcinoma (HNSC) and analyzed its potential mechanism and correlation with patient prognosis. Furthermore, a negative relationship was found between the expression level of SLC3A2 and the extent of immune cell infiltration and immune checkpoint. Differentially expressed genes (DEGs) between the high and low SLC3A2 expression groups were primarily involved in cytokine-cytokine receptor interaction and immune response. Finally, in vitro experiments demonstrated that SLC3A2 stimulates tumor cell proliferation and migration.

In conclusion, these results indicated a strong association between SLC3A2 and progression in both NPC and HNSC, suggesting it as a promising biomarker for predicting adverse prognosis in NPC and HNSC patients.

Prolonged psychological stress is closely associated with cancer due to its role in promoting the release of stress hormones through the sustained activation of the sympathetic-adrenal-medullary system. These hormones interact with receptors on inflammatory cells, leading to the activation of key signaling pathways, including the transcription factors signal transducer and activator of transcription 3 (STAT-3) and kappa-light-chain-enhancer of activated B cells (NF-κB). These factors drive the production of pro-inflammatory substances, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which can influence the initiation and progression of cancer.

This article aims to summarize how the chronic inflammatory environment induced by chronic stress promotes the initiation, progression, and invasion of cancer. By enhancing our understanding of the complex mechanisms through which stress contributes to cancer, we hope to identify new targets for cancer prevention and treatment.

Chronic stress establishes an inflammatory microenvironment by activating STAT-3 and NF-κB in inflammatory cells. This ongoing inflammation further enhances the activity of these transcription factors, which serve multiple roles: they act as pro-inflammatory agents in inflammatory cells, maintaining chronic inflammation; as oncogenic transcription factors in premalignant cells, promoting cancer initiation; and as pro-differentiation transcription factors in tumor-infiltrating immune cells, facilitating cancer progression. Additionally, the impact of chronic stress varies among different cancer types and individual responses to stress, highlighting the complexity of stress-related cancer mechanisms. Ultimately, this dynamic interplay creates a feedback loop involving IL-6, STAT-3, and TNF-α-NF-κB within the tumor microenvironment, mediating the intricate interactions between inflammation, immunity, and cancer.

Marked by iron buildup and lipid peroxidation, ferroptosis is a relatively new regulatory cell death (RCD) pathway. Many diseases like cancer, myocardial ischemia-reperfusion injury (MIRI), neurological disorders and acute renal failure (AKI) are corelated with ferroptosis. The main molecular processes of ferroptosis discovered yet will be presented here, along with the approaches in which it interacts with tumour-associated signaling pathways and its uses in systemic therapy, radiation therapy, and immunotherapy managing tumors.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, bone and cartilage damage, musculoskeletal pain, swelling, and stiffness. Inflammation is one of the key factors that induce RA. Jingfang Granule (JFG) is a traditional Chinese medicine (TCM) with significant anti-inflammatory effects. Clinical studies have confirmed that JFG can be used to treat RA, but the mechanism is still vague.

This study was designed to evaluate the protective function and the mechanism of JFG on rats with RA.

Complete Freud's Adjuvant (CFA) was used to establish a rat RA model, and JFG or Diclofenac Sodium (Dic) was orally administered. Foot swelling and hematoxylin eosin (H&E) staining were used to test the therapeutic effect of JFG on RA treatment, while ELISA kits were used to detect serum cytokines. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and reactive oxygen species (ROS) were used to evaluate oxidative stress levels. The integration of label-free proteomics, fecal short chain fatty acid (SCFA) targeted metabolomics, peripheral blood SCFA, medium and long chain fatty acid targeted metabolomics, and 16S rDNA sequencing of gut microbiota were used to screen the mechanism. Western blot technology was used to validate the results of multiple omics studies. Serum D-Lactic acid, lipopolysaccharide specific IgA antibody (LPS IgA), diamine oxidase (DAO), and colon Claudin 5 and ZO-1 were used to evaluate the intestinal barrier.

The results confirmed that JFG effectively protected rats from RA injury, which was confirmed by improved foot swelling and synovial pathology. At the same time, JFG reduced the levels of TNF-α, IL-1β, and IL-6 in serum by inhibiting the NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway in synovial tissue. Multiple omics studies indicated that JFG increased the abundance of gut microbiota and regulated the number of gut bacteria, thereby increased the levels of Acetic acid, Propionic acid, and Butyric acid in the gut and serum of RA rats, which activated AMPK to regulate fatty acid metabolism and fatty acid biosynthesis, thereby inhibited lipid oxidative stress induced ferroptosis to improve tissue damage caused by RA. Meanwhile, JFG improved the intestinal barrier by upregulating the expresses of Claudin 5 and ZO-1, which was confirmed by low concentrations of D-Lactic acid, LPS-SIgA and DAO in serum.

This study confirmed that JFG improved the disturbance of fatty acid metabolism by modulating gut microbiota and the production of fecal SCFAs to activate AMPK, and then inhibited ferroptosis caused by lipid oxidative stress in synovium tissue and prevented AR injury. This study proposes for the first time to investigate the mechanism of JFG treatment for RA from the perspective of the "Gut-joint" axis, and provides a promising approach for the treatment of RA.

The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.

Anti-cancer agent paclitaxel induces cognitive impairment. Paclitaxel can induce limited neuron apoptosis and wide scope of neuroinflammation, but its precise mechanisms remain unclear. In this study, we determined paclitaxel causes necroptosis, a programmed cell death, via activation of the RIPK1-RIPK3-MLKL signaling pathway in hippocampal neurons (HT22 cells). Flow cytometric analysis, propidium iodide staining, and western blotting techniques were used to evaluate paclitaxel-induced necroptosis. Cell viability was determined using the Cell Counting Kit-8 assay, and the Ca2+ levels were measured using a Fluo-4 AM fluorescent probe. The number of cells positive for both annexin V and propidium iodide staining was significantly higher in paclitaxel-treated than vehicle-treated HT22 cells. Additionally, the nuclei of paclitaxel-treated cells exhibited more diffused necrotic propidium iodide staining than the vehicle-treated cells. The expression of necroptosis-associated proteins, including receptor-interacting protein kinase (RIPK)1, RIPK3, mixed lineage kinase domain-like protein (MLKL), and phosphorylated (p)-MLKL, were increased following paclitaxel treatment. Treating HT22 cells with necrostatin-1, a specific inhibitor for RIPK1, effectively decreased paclitaxel-induced necroptosis through lowering intracellular Ca2+ overload. In addition, administration of necrostatin-1 to paclitaxel-treated mice rescued cognitive impairments, as assessed by novel object recognition and Morris water maze tests. Necrostatin-1 also reduced the increases in necroptosis-associated protein levels of RIPK1, RIPK3, MLKL, and p-MLKL in hippocampal tissue of paclitaxel-treated mice. Paclitaxel induces cognitive deficits through RIPK1-mediated necroptosis. The inhibition of necroptosis may be a potential therapeutic approach to reduce paclitaxel-induced cognitive deficits.

The increasing prevalence and limited therapeutic options for liver fibrosis necessitates more medical attention. Our study aims to investigate the potential molecular targets by which Moringa oleifera Lam leaf extract (Mor) and/or telmisartan (Telm) alleviate carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Liver fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 50% CCl4 (1 ml/kg) every 72 hours, for 8 weeks. Intoxicated rats with CCl4 were simultaneously orally administrated Mor (400 mg/kg/day for 8 weeks) and/or Telm (10 mg/kg/day for 8 weeks). Treatment of CCl4-intoxicated rats with Mor/Telm significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities compared to CCl4 intoxicated group (P < 0.001). Additionally, Mor/Telm treatment significantly reduced the level of hepatic inflammatory, profibrotic, and apoptotic markers including; nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), transforming growth factor-βeta1 (TGF-β1), and caspase-3. Interestingly, co-treatment of CCl4-intoxicated rats with Mor/Telm downregulated m-RNA expression of histone deacetylase 2 (HDAC2) (71.8%), and reduced protein expression of mothers against decapentaplegic homolog 3 (p-SMAD3) (70.6%) compared to untreated animals. Mor/Telm regimen also elevated p-SMAD7 protein expression as well as m-RNA expression of peroxisome proliferator-activated receptor γ (PPARγ) (3.6 and 3.1 fold, respectively p < 0.05) compared to CCl4 intoxicated group. Histopathological picture of the liver tissue intoxicated with CCl4 revealed marked improvement by Mor/Telm co-treatment. Conclusively, this study substantiated the hepatoprotective effect of Mor/Telm regimen against CCl4-induced liver fibrosis through suppression of TGF-β1/SMAD3, and HDAC2/NF-κB signaling pathways and up-regulation of SMAD7 and PPARγ expression.

Thieno[2,3-d]pyrimidine fragment is not only bioistostere to quinazoline ring but also to purines which exist in nucleic acids responsible for several key biological processes of the living cells, thus it is of a great interest for many researchers. Thieno[2,3-d]pyrimidine ring has become an important scaffold for different compounds with versatile pharmacological activities including anticancer. These compounds exert their anticancer activity through variant mechanisms of action; one of these is the induction of different programmed cell death types as apoptosis and necroptosis which is an effective approach for cancer treatment. This review highlights the different synthetic approaches of recent thieno[2,3-d]pyrimidine analogs along with their anticancer significance through induction of apoptotic or necroptotic cell death with illustration of the structure-activity relationship (SAR).

Nephropathy is the microvascular complication of diabetes mellitus and is the leading cause of chronic kidney disease. This review discusses the implications of receptor-interacting protein kinase (RIPK) family members and their regulation of inflammation and cell death pathways in the initiation and progression of diabetic kidney disease. Hyperglycemia leads to reactive oxygen species (ROS) generation and RIPK1 overexpression, the first regulator of necroptosis. Further, RIPK1 can form complex I to promote nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathway activation or complex II to cause programmed cell death in the kidneys. The rise in RIPK1 level upon ROS generation declines the apoptosis regulators' level while the necroptosis regulators' level is boosted. Necroptosis is a programmed or controlled necrosis-type cell death pathway executed by RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL) proteins, and recent research suggests its importance in diabetic nephropathy. In necroptosis, RIPK1 and RIPK3 interrelate with their RIP homotypic interaction motif (RHIM) domains and cause the recruitment of MLKL. Next, MLKL gets oligomerized, migrate towards the plasma membrane, and causes its rupture. We emphasized different research studies on drugs highlighting the nephroprotective effects via regulating the RIPKs. We hope that the conclusions of this review may provide new strategies for diabetic kidney disease treatment and promising targets for drug development based on necroptosis.

Stroke, ischemic or hemorrhagic, triggers a complex and coordinated glial response, which, to a large extent, defines the progression and outcome of this focal damage of the nervous tissue. Massive cell death in the infarction core results in a release of damage-associated molecular patterns, which, together with blood-borne factors entering the brain through either ruptured vessels or through compromised blood-brain barrier, trigger reactive gliosis. Microglia are the first to migrate toward the lesion, proliferate, and phagocytose cellular debris in and around the infarct core. Reactive astrogliosis occurs around the margins of the infarct core and is characterized by astrocytic proliferation, morphologic remodeling with loss of territorial domain segregation, and transcriptional reprogramming into wound repair astrocytes that form a periinfarct border that protects the healthy tissue and assists postlesional regeneration.

Idiopathic inflammatory myopathies (IIM) are a group of systemic autoimmune diseases characterized by muscle weakness and elevated serum creatine kinase levels. Recent research has highlighted the role of the innate immune system, particularly inflammasomes, in the pathogenesis of IIM. This review focuses on the role of inflammasomes, specifically NLRP3 and AIM2, and their associated proteins in the development of IIM. We discuss the molecular mechanisms of pyroptosis, a programmed cell death pathway that triggers inflammation, and its association with IIM. The NLRP3 inflammasome, in particular, has been implicated in muscle fiber necrosis and the subsequent release of damage-associated molecular patterns (DAMPs), leading to inflammation. We also explore the potential therapeutic implications of targeting the NLRP3 inflammasome with inhibitors such as glyburide and MCC950, which have shown promise in reducing inflammation and improving muscle function in preclinical models. Additionally, we discuss the role of caspases, particularly caspase-1, in the canonical pyroptotic pathway associated with IIM. The understanding of these mechanisms offers new avenues for therapeutic intervention and a better comprehension of IIM pathophysiology.

Within the last decade, the scientific community has witnessed the importance of ferroptosis as a novel cascade of molecular events leading to cellular decisions of death distinct from apoptosis and other known forms of cell death. Notably, such non- apoptotic and iron-dependent regulated cell death has been found to be intricately linked to several physiological processes as well as to the pathogenesis of various diseases. To this end, recent data support the notion that a potential molecular connection between ferroptosis and inherited bone marrow failure (IBMF) in individuals with ribosomopathies may exist. In this review, we suggest that in ribosome-related IBMFs the identified mutations in ribosomal proteins lead to changes in the ribosome composition of the hematopoietic progenitors, changes that seem to affect ribosomal function, thus enhancing the expression of some mRNAs subgroups while reducing the expression of others. These events lead to an imbalance inside the cell as some molecular pathways are promoted while others are inhibited. This disturbance is accompanied by ROS production and lipid peroxidation, while an additional finding in most of them is iron accumulation. Once lipid peroxidation and iron accumulation are the two main characteristics of ferroptosis, it is possible that this mechanism plays a key role in the manifestation of IBMF in this type of disease. If this molecular mechanism is further confirmed, new pharmacological targets such as ferroptosis inhibitors that are already exploited for the treatment of other diseases, could be utilized to improve the treatment of ribosomopathies.

In this study, the copper(II) complex [Cu(chromoneTSC)Cl2]•0.5H2O•0.0625C2H5OH (where chromoneTSC = (E)-N-Ethyl-2-((4-oxo-4H-chromen-3-yl)methylene)-hydrazinecarbothioamide) was synthesized and characterized; then used to carry out in vitro studies in combination with berberine chloride (BBC). The ligand and complex were characterized by elemental analysis, FTIR and NMR (1H and 13C) spectroscopy, and conductivity measurements. The cytotoxic effect was analyzed by using the CCK-8 viability assay in cancer MDA-MB-231 VIM RFP and non-cancer MCF-10A cell lines. The IC50 values for the complex and BBC were 21.2 ±1.6 and 48.3 ± 2.4 μM, respectively at 24 h incubation, while the IC50 value of the combination treatment was 9.3 ± 1.5 in cancer cells. The co-treatment group significantly increased the number of cells in G2 phase, indicating the growth arrest of cancer cells. Moreover, the combination group showed induction of both intrinsic and extrinsic apoptotic pathways. There was also a study on the effect of the combination treatment on receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL) as biomarkers of necroptosis. The results showed activation of necroptosis after treatment with the combination of the copper complex and BBC via the activation of RIPK3-MLKL pathway.

Ischemia-reperfusion injury (IRI) is detrimental to kidney transplants and may contribute to poor long-term outcomes of transplantation. Programmed cell death (PCD), a regulated cell death form triggered by IRI, is often indicative of an unfavorable prognosis following transplantation. However, given the intricate pathophysiology of IRI and the considerable variability in clinical conditions during kidney transplantation, the specific patterns of cell death within renal tissues remain ambiguous. Consequently, accurately predicting the outcomes for transplanted kidneys continues to be a formidable challenge.

Eight Gene Expression Omnibus datasets of biopsied transplanted kidney samples post-IRI and 1,548 PCD-related genes derived from 18 PCD patterns were collected in our study. Consensus clustering was performed to identify distinct IRI subtypes based on PCD features (IRI PCD subtypes). Differential enrichment analysis of cell death, metabolic signatures, and immune infiltration across these subtypes was evaluated. Three machine learning algorithms were used to identify PCD patterns related to prognosis. Genes associated with graft loss were screened for each PCD type. A predictive model for graft loss was constructed using 101 combinations of 10 machine learning algorithms.

Four IRI subtypes were identified: PCD-A, PCD-B, PCD-C, and PCD-D. PCD-A, characterized by high enrichment of multiple cell death patterns, significant metabolic paralysis, and immune infiltration, showed the poorest prognosis among the four subtypes. While PCD-D involved the least kind of cell death patterns with the features of extensive activation of metabolic pathways and the lowest immune infiltration, correlating with the best prognosis in the four subtypes. Using various machine learning algorithms, 10 cell death patterns and 42 PCD-related genes were identified as positively correlated with graft loss. The predictive model demonstrated high sensitivity and specificity, with area under the curve values for 0.5-, 1-, 2-, 3-, and 4-year graft survival at 0.888, 0.91, 0.926, 0.923, and 0.923, respectively.

Our study explored the comprehensive features of PCD patterns in transplanted kidney samples post-IRI. The prediction model shows great promise in forecasting graft loss and could aid in risk stratification in patients following kidney transplantation.

In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.