Tissue homeostasis relies on a delicate balance between cell death and proliferation. Apoptosis plays a key role not only in removing damaged cells but also in promoting tissue recovery through a process known as apoptosis-induced proliferation (AiP). This review highlights how caspases, c-Jun N-terminal Kinase (JNK), and Reactive Oxygen Species (ROS) bridge cell death and proliferation, as revealed through studies using Drosophila as a model organism. We also compare these findings with advances in other model systems and discuss their broader implications for tissue regeneration and tumorigenesis.

The landmark discovery of the BCL-2 gene and then its function marked the identification of inhibition of apoptotic cell death as a crucial novel mechanism driving cancer development and launched the quest to discover the molecular control of apoptosis. This work culminated in the generation of specific inhibitors that are now in clinical use, saving and improving tens of thousands of lives annually. Here, some of the original players of this story, describe the sequence of critical discoveries. The t(14;18) chromosomal translocation, frequently observed in follicular lymphoma, allowed the identification and the cloning of a novel oncogene (BCL-2) juxtaposed to the immunoglobulin heavy chain gene locus (IgH). Of note, BCL-2 acted in a distinct manner as compared to then already known oncogenic proteins like ABL and c-MYC. BCL-2 did not promote cell proliferation but inhibited cell death, as originally shown in growth factor dependent haematopoietic progenitor cell lines (e.g., FDC-P1) and in Eμ-Myc/Eμ-Bcl-2 double transgenic mice. Following a rapid expansion of the BCL-2 protein family, the Abbott Laboratories solved the first structure of BCL-XL and subsequently the BCL-XL/BAK peptide complex, opening the way to understanding the structures of other BCL-2 family members and, finally, to the generation of inhibitors of the different pro-survival BCL-2 proteins, thanks to the efforts of Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude and Gilead. Although the BCL-2 inhibitor Venetoclax is in clinical use and inhibitors of BCL-XL and MCL-1 are undergoing clinical trials, several questions remain on whether therapeutic windows can be achieved and what other agents should be used in combination with BH3 mimetics to achieve optimal therapeutic impact for cancer therapy. Finally, the control of the expression of BH3-only proteins and pro-survival BCL-2 family members needs to be better understood as this may identify novel targets for cancer therapy. This story is still not concluded!

Klotho, initially introduced as an anti-aging protein, is expressed in the brain, pancreas, and most prominently in the kidney. The two forms of Klotho (membrane-bound and soluble form) have diverse pharmacological functions such as anti-inflammatory, anti-oxidative, anti-fibrotic, tumour-suppressive etc. The membrane-bound form plays a pivotal role in maintaining kidney homeostasis by regulating fibroblast growth factor 23 (FGF 23) signalling, vitamin D metabolism and phosphate balance. Klotho deficiency has been linked with significantly reduced protection against various kidney pathological phenotypes, including diabetic kidney disease (DKD), which is a major cause of chronic kidney disease leading to end-stage kidney disease. Owing to the pleiotropic actions of klotho, it has shown beneficial effects in DKD by tackling the complex pathophysiology and reducing kidney inflammation, oxidative stress, as well as fibrosis. Moreover, the protective effect of klotho extends beyond DKD in other pathological conditions, including cardiovascular diseases, alzheimer's disease, cancer, inflammatory bowel disease, and liver disease. Therefore, this review summarizes the relationship between Klotho expression and various diseases with a special emphasis on DKD, the distinct mechanisms and the potential of exogenous Klotho supplementation as a therapeutic strategy. Future research into exogenous Klotho could unravel novel treatment avenues for DKD and other diseases.

Characterized by a poor prognosis and survivability, head and neck squamous cell carcinoma (HNSCC) is an aggressive neoplastic condition with a propensity for recurrence where the development of chemoresistance adversely affects the prognostic outcome. Recently, it was shown that circular RNAs (circRNAs) augment the cellular survivability and chemoresistance of malignant cells. Hence, biomarkers for early detection of chemoresistance in these patients can significantly aid in preventing a poor prognostic outcome.

The present study aimed to systematically identify circRNAs that play a vital role in the development of chemoresistance in HNSCC and understand their mechanisms of action in HNSCC chemoresistance.

The protocol was prospectively registered on PROSPERO with protocol no. CRD42024532291. A six-stage methodological and PRISMA recommendations were followed for the review.

13 studies were identified which yielded 13 circRNAs which have been investigated for their role in the chemoresistance in HNSCC. Of these, 11 circRNAs were reported to be upregulated while only 2 circRNAs were found to be downregulated. Moreover, we found that circRNAs can modulate autophagy (circPARD3, circPKD2, circAP1M2 and circPGAM1), apoptosis (circ-ILF2, circANKS1B, circTPST2, circPUM1 and circ_0001971), drug efflux (circ-ILF2, has_circ_0005033 and circTPST2), EMT (circANKS1B, circCRIM1, circ_0001971), tumor microenvironment (circ-ILF2. circ-ILF2, circCRIM1 and circTPST2), DNA damage (circTPST2) and malignant potential (hsa_circ_0000190 and hg19_ circ_0005033).

The present study identified 13 circRNAs which may serve as biomarkers for prognosis as well as response to chemotherapy in HNSCC.

PROSPERO, identifier CRD42024532291.

The apoptotic effects of odoroside A on lung cancer cells were studied in our project. We also supported and extended our experimentally-proven results via bioinformatics analysis on human lung cancer tissues.

In vitro studies were conducted using the A549 cell line. Cell proliferation was evaluated through a CCK-8 assay. For gene expression analysis, the qRT-PCR method was used, while CASP3 protein levels were detected using Western blotting and ELISA. Moreover, the oxidant status of cells was determined by measuring TAS and TOS levels. To construct a protein-protein interaction network, STRING analysis was performed. For the determination of differential expression of apoptosis-related genes, the GEPIA tool was utilized. Kaplan-Meier plots with overall survival, disease-specific survival and progression free intervals were obtained from UCSC Xena to evaluate the prognostic value of caspases.

The gene expression levels of CASP3, CASP7, CASP8, CASP9, FAS, and FADD were elevated between 4-16 fold in Odo A-treated lung cancer cells compared to controls. CASP3 protein expression was significantly higher in Odo A-treated cancerous cells than the control group. Low TAS (0.5700 ± 0.0067 in Odo A vs. 0.6437 ± 0.0151 in control) and high TOS (0.82800 ± 0.0208 in Odo A vs. 0.6263 ± 0.0258 in control) levels as well as high OSI values (1.4531 ± 0.0414 in Odo A vs. 0.9748 ± 0.0539 in control) were obtained. Correlogram and protein-protein network analyses suggested strong correlations and interactions among target genes. Lastly, Kaplan-Meier analysis showed no prognostic value of caspases, but potential therapeutic targets in lung cancer.

Anti-cancer, prooxidative and therapeutic effects of Odo A on lung cancer cells were shown in our study. These data were supported and extended via computational analyses that we performed. In conclusion, Odo A could be used in clinics to treat patients with lung cancer.

Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.

Regulated cell death is integral to sculpting the developing brain, yet the relative contributions of extrinsic apoptosis and necroptosis remain unclear. Here, we leverage single-cell mass cytometry (CyTOF) to characterize the cellular landscape of the mouse telencephalon in wild-type (WT), RIPK3 knockout (RIPK3 KO), and RIPK3/Caspase-8 double knockout (DKO) mice. Strikingly, combined deletion of RIPK3 and Caspase-8 leads to a 12.6% increase in total cell count, challenging the prevailing notion that intrinsic apoptosis exclusively governs developmental cell elimination. Detailed subpopulation analysis reveals that DKO mice display selective enrichment of Tbr2⁺ intermediate progenitors and endothelial cells, underscoring distinct, cell type-specific roles for extrinsic apoptotic and necroptotic pathways. These findings provide a revised framework for understanding the coordinated regulation of cell number during telencephalic development and suggest potential mechanistic links to neurodevelopmental disorders characterized by aberrant cell death.

Differentiation from neural progenitor to mature neuron requires a metabolic switch, whereby mature neurons become almost entirely dependent upon oxidative phosphorylation (OXPHOS) for ATP production. Although more efficient with respect to ATP production, OXPHOS produces additional reactive oxygen species, as compared to glycolysis; thus, endogenous mechanisms to quench free radicals are essential for the maintenance of neuronal health. Melatonin is synthesized in neuronal mitochondria and has a dual role as a free radical scavenger and as an inhibitor of mitochondrial-triggered cell death and proinflammatory pathways. Previously, we showed that loss of endogenous melatonin induced mitochondrial DNA (mtDNA) and cytochrome c (CytC) release triggering pathological inflammation and cell death pathways, respectively. Here we find that in mature neurons, but not undifferentiated neuronal cells, melatonin deficiency altered metabolic reprogramming in aralkylamine N-acetyltransferase knockout (AANAT-KO) neurons as compared with neurons expressing AANAT. Interestingly, there are no differences in neural progenitors regardless of AANAT status. In addition, AANAT-KO deficiency elevated BAK and BAX levels in AANAT-KO neurons. Further, we found that exogenous melatonin treatment of AANAT-KO cells during differentiation into mature neurons rescued metabolic reprogramming defects and restored normal BAK/BAX levels. Thus, we demonstrated that the metabolic reprogramming and subsequent consequences of the switch to OXPHOS that normally occurs during neuronal maturation are compromised by melatonin deficiency and rescued by melatonin supplementation.

This study attempts to develop a novel apoptosis-related predictive model for cervical cancer. Differentially expressed apoptosis-related genes were identified using TCGA, GEO, and MSigDB databases. A 13-gene prognostic model was constructed using multiple regression analyses. The low-risk group exhibited low tumor purity and high ESTIMATE and immune scores. Most of the immune checkpoints in the low-risk group were expressed at higher levels than those in the high-risk group. The low-risk group also had relatively more infiltrating immune cells. An independent prognostic model pertaining to cell apoptosis has been built by this work, which performs well in prediction.

Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes in a variety of diseases including asthma. In this study, we reported the identification of lncRNA-AK007111 as an essential modulator of mast cell apoptosis and investigated its potential mechanism.

RNA-seq profiling and transcriptome sequencing technology were adopted to screen for differentially expressed genes. Transfection was done by small interfering RNAs (siRNAs) to down-regulate lncRNA-AK007111 and Modulator of apoptosis 1 (MOAP1). Starvation was used to induce apoptosis. The apoptotic rate was measured by flow cytometry. Western Blot was conducted to detect the expression of apoptosis-related proteins.

LncRNA-AK007111 was highly expressed in IgE/Ag-mediated activation of mast cells. Down-regulation of LncRNA-AK007111 promoted apoptosis of mast cells. Down-regulation of MOAP1 attenuated apoptosis in mast cells induced by the down-regulation of lncRNA-AK007111.

LncRNA-AK007111 may be a potential regulator of mast cell apoptosis by interaction with MOAP1.

The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRR- and guard protein-dependent defenses in response to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) respond in distinct ways to bacterial virulence activities. In macrophages, the bacterial pathogen Legionella pneumophila deploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate its robust intracellular replication. In contrast, T4SS activity triggers rapid DC death that potently restricts Legionella replication within this cell type. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single cell level. Initially, a subset of DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis and release IL-1 β early during infection. At later timepoints, a separate DC population undergoes apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the levels of the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict Legionella replication in DCs. Collectively, our work suggests a model where Mcl-1 and cFLIP guard host translation in DCs, and that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to Legionella infection.

Cancer remains a leading cause of mortality worldwide, accounting for approximately 10 million deaths annually. Standard treatments, including surgery, radiotherapy, and chemotherapy, often result in damage to healthy cells and severe toxic side effects. In recent years, antisense technology therapeutics, which interfere with RNA translation through complementary base pairing, have emerged as promising approaches for cancer treatment. Despite the availability of various antisense oligonucleotide (ASO) drugs on the market, challenges such as poor active targeting and susceptibility to clearance by circulating enzymes remain. Compared with other delivery systems, lipid nanovesicle (LNV) delivery systems offer a potential solution that uniquely enhances ASO targeting and stability. Studies have shown that LNVs can increase the accumulation of ASOs in tumor sites several-fold, significantly reducing systemic toxic reactions and demonstrating increased therapeutic efficiency in preclinical models. Additionally, LNVs can protect ASOs from enzymatic degradation within the body, extending their half-life and thus enhancing their therapeutic effects. This paper provides a comprehensive review of recent examples and applications of LNV delivery of ASOs in cancer treatment, highlighting their unique functions and outcomes. Furthermore, this paper discusses the key challenges and potential impacts of this innovative approach to cancer therapy.

The gut barrier is the first line of defense against harmful substances and pathogens in the intestinal tract. The balance of proliferation and apoptosis of intestinal epithelial cells (IECs) is crucial for maintaining the integrity of the intestinal mucosa and its function. However, oxidative stress and inflammation can cause DNA damage and abnormal apoptosis of the IECs, leading to the disruption of the intestinal epithelial barrier. This, in turn, can directly or indirectly cause various acute and chronic intestinal diseases. In recent years, there has been a growing understanding of the vital role of dietary ingredients in gut health. Studies have shown that certain amino acids, fibers, vitamins, and polyphenols in the diet can protect IECs from excessive apoptosis caused by oxidative stress, and limit intestinal inflammation. This review aims to describe the molecular mechanism of apoptosis and its relationship with intestinal function, and to discuss the modulation of IECs' physiological function, the intestinal epithelial barrier, and gut health by various nutrients. The findings of this review may provide a theoretical basis for the use of nutritional interventions in clinical intestinal disease research and animal production, ultimately leading to improved human and animal intestinal health.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 enhances spontaneous apoptosis in cells, but its effects on HIV-1-induced apoptosis and the underlying mechanisms remain unknown. Here we uncover a new mechanism by which SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells through the mitochondrial pathway. We found that endogenous SAMHD1 enhances apoptosis levels induced by HIV-1 infection in dividing THP-1 cells. Mechanistically, SAMHD1 expression decreases the mitochondrial membrane potential and promotes cytochrome c release induced by HIV-1 infection in THP-1 cells, thereby enhancing mitochondrial apoptotic pathway. SAMHD1-enhanced apoptosis is associated with increased expression of the pro-apoptotic protein BCL-2-interacting killer (BIK) in cells. We further demonstrated that BIK contributes to SAMHD1-enhanced apoptosis during HIV-1 infection. Overall, our results reveal an unappreciated regulatory mechanism of SAMHD1 in enhancing HIV-1-induced apoptosis via the mitochondrial pathway in monocytic cells.

The B-cell lymphoma-2 (Bcl-2) protein family plays a crucial role as a regulator in the process of apoptosis. There is a substantial body of evidence indicating that the upregulation of antiapoptotic Bcl-2 proteins is prevalent in several cancer cell lines and original tumour tissue samples. This phenomenon plays a crucial role in enabling tumour cells to avoid apoptosis, hence facilitating the development of resistant cells against chemotherapy. Therefore, the success rate of chemotherapy for cancer can be enhanced by the down-regulation of anti-apoptotic Bcl-2 proteins. Furthermore, the indole structural design is commonly found in a variety of natural substances and biologically active compounds, particularly those that possess anti-cancer properties. Due to its distinctive physicochemical and biological characteristics, it has been highly regarded as a fundamental framework in the development and production of anti-cancer drugs. As a result, a considerable range of indole derivatives, encompassing both naturally occurring and developed compounds, have been identified as potential candidates for the treatment of cancer. Several of these derivatives have advanced to clinical trials, while others are already being used in clinical settings. This emphasizes the significant role of indole in the field of research and development of anti-cancer therapeutics. This study provides an overview of apoptosis and the structural characteristics of Bcl-2 family proteins, and mainly examines the present stage and recent developments in Bcl-2 inhibitors with an indole scaffold embedded in their structure.

Korean Red ginseng has emerged as a potent candidate in the fight against various viral infections, demonstrating significant efficacy both in vitro and in vivo, particularly against influenza A viruses. Despite substantial evidence of its antiviral properties, the detailed molecular mechanisms through which it reduces viral lethality remain insufficiently understood. Our investigations have highlighted the superior effectiveness of Korean Red ginseng against influenza viruses, outperforming its effects on numerous other viral strains. We aim to uncover the specific mechanisms by which Korean Red ginseng exerts its antiviral effects, focusing on influenza A viruses. Our prior studies have identified the role of Z-DNA-binding protein 1 (ZBP1), a signaling complex involved in inducing programmed cell death in response to influenza virus infection. Given the critical role of ZBP1 as a sensor for viral nucleic acid, we hypothesize that Korean Red ginseng may modulate the ZBP1-derived cell death pathway. This interaction is anticipated to enhance cell death while concurrently suppressing viral protein expression, offering novel insights into the antiviral mechanism of Korean Red ginseng against influenza A viruses.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common and serious clinical lung disease characterized by extensive alveolar damage and inflammation leading to impaired gas exchange. Alveolar macrophages (AMs) maintain homeostatic properties and immune defenses in lung tissues. Several studies have reported that AMs are involved in and regulate ALI/ARDS onset and progression via different regulated cell death (RCD) programs, such as pyroptosis, apoptosis, autophagic cell death, and necroptosis. Notably, the effects of RCD in AMs in disease are complex and variable depending on the environment and stimuli. In this review, we provide a comprehensive perspective on how regulated AMs death impacts on ALI/ARDS and assess its potential in new therapeutic development. Additionally, we describe the crosstalk between different RCD types in ALI, and provide new perspectives for the treatment of ALI/ARDS and other severe lung diseases.

Caspase-2, a highly conserved member of the caspase family, is considered an initiator caspase that triggers apoptosis in response to some cellular stresses. Previous studies suggest that an intracellular multi-protein complex PIDDosome, induced by genotoxic stress, serves as a platform for caspase-2 activation. Due to caspase-2's inability to process effector caspases, however, the mechanism underlying caspase-2-mediated cell death upon PIDDosome activation remains unclear. Here, we conducted an unbiased genome-wide genetic screen and identified that the Bcl2 family protein BID is required for PIDDosome-induced, caspase-2-mediated apoptosis. PIDDosome-activated caspase-2 directly and functionally processes BID to signal the mitochondrial pathway for apoptosis induction. In addition, a designed chemical screen identified a compound, HUHS015, which specifically activates caspase-2-mediated apoptosis. HUHS015-stimulated apoptosis also requires BID but is independent of the PIDDosome. Through extensive structure-activity relationship efforts, we identified a derivative with a potency of ~60 nmol/L in activating caspase-2-mediated apoptosis. The HUHS015-series of compounds act as efficient agonists that directly target the interdomain linker in caspase-2, representing a new mode of initiator caspase activation. Human and mouse caspase-2 differ in two crucial residues in the linker, rendering a selectivity of the agonists for human caspase-2. The caspase-2 agonists are valuable tools to explore the physiological roles of caspase-2-mediated cell death and a base for developing small-molecule drugs for relevant diseases.

T-cell Acute Lymphoblastic Leukemia (T-ALL) is a highly aggressive form of ALL with at least 25% relapse rates. The high relapse rates are often linked to poor prognoses. More detailed studies for novel therapeutic targets for the treatment of T-ALL are required as the genetic and transcriptomic data currently available on T-ALL pathophysiology is insufficient. Long non-coding RNAs are emerging as important players in the regulation of tumour proliferation and metastasis. Studies on various cancers have revealed their potential as biomarkers and therapeutic targets in treatment. This review describes the characterization, biosynthesis, and role of long non-coding RNA in T-ALL and highlights their potential as next generation molecule in development of promising diagnostic, prognostic and/or therapeutic markers.

The aim of this study was to explain the mechanism underlying the liver injury of juvenile largemouth bass Micropterus salmoides in response to high-starch diet intake. Three diets were formulated with different starch levels, being abbreviated as treatment LS (low starch, 8.13% starch), MS (medium starch, 14.1% starch), and HS (high starch, 20.1% starch), respectively. Fish were fed with their respective diets to apparent satiation for 56 days. The results showed that growth retardation of the HS fish was associated with the reduction in feed intake rather than feed utilization. Histological evaluation of the livers showed that vacuolization was the most prevalent characteristic in the MS fish, while ballooning degeneration, apoptosis, fibrosis, and inflammation were observed in the HS fish. Transcriptome profiling suggested that liver inflammation was mediated by Tlr signal transduction, which activated the Pi3k/Akt/Nfκb signaling axis to promote the release of proinflammatory factors including Il-8 and Ip-10. Hepatocyte apoptosis was mediated by the extrinsic pathway through death receptors including Fas and Tnfr, which coordinately activated the Fadd/caspase-8 death signaling axis. An autonomous inhibition program was identified to counteract the apoptosis signal, and the PI3K/Akt signaling pathway might play an important role in this process through regulating the expression of iap and diablo. Liver fibrosis was mediated through the Tgf-β and Hh signaling pathways. Upon secretion, Tgf-β1/3 bound to TgfβrI/II complex on the liver cell membrane, which induced the phosphorylation of downstream Smad2/3. When Hh interacted with the membrane receptor Ptc, Smo was activated to initiate signaling, driving the activation of Gli. The activation of both Smad2/3 and Gli promoted their nuclear translocation thereby regulating the transcription of target genes, which resulted in the activation and proliferation of HSCs. The activated HSCs constantly expressed colla1 and ctgf, which facilitated substantial accumulation of ECM. It should be noted that the molecular mechanism of liver injury in this study was speculated from the transcriptome data thus further experimental verification is warranted for this speculation.

Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Despite the success of early interventions, such as tissue-type plasminogen activator administration and mechanical thrombectomy, many patients continue to experience persistent neurological deficits. The pathophysiology of IS is multifaceted, encompassing excitotoxicity, oxidative and nitrosative stress, inflammation, and blood-brain barrier disruption, all of which contribute to neural cell death, further complicating the treatment of IS. Recently, extracellular vesicles (EVs) secreted naturally by various cell types have emerged as promising therapeutic agents because of their ability to facilitate selective cell-to-cell communication, neuroprotection, and tissue regeneration. Furthermore, engineered EVs, designed to enhance targeted delivery and therapeutic cargo, hold the potential to improve their therapeutic benefits by mitigating neuronal damage and promoting neurogenesis and angiogenesis. This review summarizes the characteristics of EVs, the molecular mechanisms underlying IS pathophysiology, and the emerging role of EVs in IS treatment at the molecular level. This review also explores the recent advancements in EV engineering, including the incorporation of specific proteins, RNAs, or pharmacological agents into EVs to enhance their therapeutic efficacy.

Heart failure (HF) represents a serious manifestation or advanced stage of various cardiac diseases. HF continues to impose a significant global disease burden, characterized by high rates of hospitalization and fatality. Furthermore, the pathogenesis and pathophysiological processes underlying HF remain incompletely understood, complicating its prevention and treatment strategies. One significant pathophysiological mechanism associated with HF is the systemic inflammatory response. PANoptosis, a novel mode of inflammatory cell death, has been extensively studied in the context of infectious diseases, neurodegenerative disorders, cancers, and other inflammatory conditions. Recent investigations have revealed that PANoptosis-related genes are markedly dysregulated in HF specimens. Consequently, the PANoptosis-mediated inflammatory response may represent a potential mechanism and therapeutic target for HF. This paper conducts a comprehensive analysis of the molecular pathways that drive PANoptosis. We discuss its role and potential therapeutic targets in HF, thereby providing valuable insights for clinical treatment and the development of novel therapies.

The mechanisms of CD95 (Fas/APO-1)-mediated extrinsic apoptotic pathway in cancer cells have been extensively studied. The majority of human cells express CD95, but not all these cells can induce extrinsic apoptosis. Accumulating evidence has shown that CD95 is a multifunctional protein, and its stimulation can also elicit non-apoptotic or even survival signals. It has become clear that under certain cellular contexts, due to the various checkpoints, CD95 activation can trigger both apoptotic and non-apoptotic signals. The crosstalk of death and survival signals may occur at different levels of signal transduction. The strength of the CD95 stimulation, initial levels of anti-apoptotic proteins, and posttranslational modifications of the core DISC components have been proposed to be the most important factors in the life/death decisions at CD95. Successful therapeutic targeting of CD95 signaling pathways will require a better understanding of the crosstalk between CD95-induced apoptotic and cell survival pathways. In this review, in order to gain a systematic understanding of the crosstalk between CD95-mediated apoptosis and non-apoptotic signaling, we will discuss these issues in a step-by-step way.

Centrosomes are membrane-less organelles that orchestrate a wide array of biological functions by acting as microtubule organizing centers. Here, we report that caspase-2-driven apoptosis is elicited in blood cells failing cytokinesis and that extra centrosomes are necessary to trigger this cell death. Activation of caspase-2 depends on the PIDDosome multi-protein complex, and priming of PIDD1 at extra centrosomes is necessary for pathway activation. Accordingly, loss of its centrosomal adapter, ANKRD26, allows for cell survival and unrestricted polyploidization in response to cytokinesis failure. Mechanistically, cell death is initiated upstream of mitochondria via caspase-2-mediated processing of the BCL2 family protein BID, driving BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Remarkably, BID-deficient cells enforce apoptosis by engaging p53-dependent proapoptotic transcriptional responses initiated by caspase-2. Consistently, BID and MDM2 act as shared caspase-2 substrates, with BID being kinetically favored. Our findings document that the centrosome limits its own unscheduled duplication by the induction of PIDDosome-driven mitochondrial apoptosis to avoid potentially pathogenic polyploidization events.

Karyoptosis is a type of regulated cell death (RCD) characterized by explosive nuclear rupture caused by a loss of nuclear membrane integrity, resulting in the release of genomic DNA and other nuclear components into the cytosol and extracellular environment. The mechanism underlying karyoptosis involves a delicate balance between the following forces: the expansion force exerted by the tightly packed DNA in the nucleus, the resistance provided by the nuclear lamina at the inner nuclear membrane (INM), and the tensile force from the cytoskeleton that helps position the nucleus at the center of the cytoplasm, allowing it to remain maximally expanded. In addition, CREB3, a type II integral membrane protein with DNA-binding ability, tethers chromatin to the INM, providing a tightening force through chromatin interactions that prevent nuclear membrane rupture. UVB radiation can trigger this process, inducing CREB3-FL cleavage and producing CREB3-CF. Therefore, UVB acts as an intrinsic factor in the induction of karyoptosis. Importantly, biochemical analysis of RCD markers shows that karyoptosis is distinct from other forms of cell death, such as apoptosis, autophagy, necroptosis, and pyroptosis. This review explores the mechanisms involved in maintaining nuclear membrane integrity and the role of CREB3 in triggering karyoptosis and provides brief suggestions on the potential implications for targeting cancer cells.

Oxidative stress and mitochondrial dysfunction play critical roles in neurodegenerative diseases. Glutathione (GSH), a key brain antioxidant, helps to neutralize reactive oxygen species (ROS) and maintain redox balance. We investigated the effectiveness of L-cysteine (L-Cys) in preventing apoptosis induced by the ROS generator 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) in mouse hippocampal neuronal HT22 cells, as well as alleviating memory and cognitive impairments caused by the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) in mice. DMNQ-induced apoptotic events in HT22 cells, including elevated cytosolic and mitochondrial ROS levels, DNA fragmentation, endoplasmic reticulum stress, and mitochondrial damage-mediated apoptotic pathways were dose-dependently abrogated by L-Cys (0.5-2 mM). The reduced intracellular GSH level, caused by DMNQ treatment, was restored by L-Cys cotreatment. Although L-Cys did not significantly restore GSH in the presence of BSO, it prevented DMNQ-induced ROS elevation, mitochondrial damage, and apoptosis. Furthermore, compared to N-acetylcysteine and GSH, L-Cys had higher 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid radical-scavenging activity. L-Cys also restored mitochondrial respiration capacity in DMNQ-treated HT22 cells by reversing mitochondrial fission-fusion dynamic balance. BSO administration (500 mg/kg/day) in mice led to neuronal deficits, including memory and cognitive impairments, which were effectively mitigated by oral L-Cys (15 or 30 mg/kg/day). L-Cys also reduced BSO-induced ROS levels in the mice hippocampus and cortex. These findings suggest that even though it does not contribute to intracellular GSH synthesis, exogenous L-Cys protects neuronal cells against oxidative stress-induced mitochondrial damage and apoptosis, by acting as a ROS scavenger, which is beneficial in ameliorating neurocognitive deficits caused by oxidative stress.

Lung disease development involves multiple cellular processes, including inflammation, cell death, and proliferation. Research increasingly indicates that autophagy and its regulatory proteins can influence inflammation, programmed cell death, cell proliferation, and innate immune responses. Autophagy plays a vital role in the maintenance of homeostasis and the adaptation of eukaryotic cells to stress by enabling the chelation, transport, and degradation of subcellular components, including proteins and organelles. This process is essential for sustaining cellular balance and ensuring the health of the mitochondrial population. Recent studies have begun to explore the connection between autophagy and the development of different lung diseases. This article reviews the latest findings on the molecular regulatory mechanisms of autophagy in lung diseases, with an emphasis on potential targeted therapies for autophagy.

From its earliest characterization, it has been recognized that there is a role for regulated (programmed) cell death in cancer. As our understanding of the different types of programmed cell death processes and their molecular control has advanced, so have the technologies that allow us to manipulate these processes to, for example, fight against cancer. In this review, we describe the roles of the different forms of regulated cell death in the development of cancer as well as their potential therapeutic exploitation. In that vein, we explore the development and use of BH3-mimetics, a unique class of drugs that can directly activate the apoptotic cell death machinery to treat cancer. Finally, we address key challenges that face the field to improve the use of these therapeutics and the efforts that are being undertaken to do so.

TRAIL, a member of the TNF family, is expressed in tumor and tumor surrounding tissue in many solid organ cancers. While the induction of tumor-specific apoptosis in correlation with cytokine stimulation may cause anti-tumoral effects, the pro-tumorigenic effects of its expression by tumor surrounding tissue members have been reported in the literature. In our study, it was aimed to evaluate the effect of the gene variant of TRAIL on soluble levels in patients with colorectal cancer (CRC) on the molecular pathological axis. TRAIL C1595 gene variant PCR-RFLP and sTRAIL levels were determined by ELISA in age and sex adjusted CRC and control groups. It was determined that CT carriage was high in patients without perineural invasion and sTRAIL levels were approximately 2.72 times lower than CC in patients with CT in this group (p < 0.05). Similarly, sTRAIL level was found to be high in patients with CC genotype in CRC without lymph node metastas. It was determined that CT carriage was high in patients without perineural invasion and sTRAIL levels were approximately 2.49 times lower than CC in patients with CT in this group.is (p < 0.05). We think that TRAIL C1595T in CRC can change sTRAIL levels in the clinicopathological axis in advanced stages such as metastasis and invasion, but both are not independent risk factors.

Chemotherapy drugs efficiently eradicate rapidly dividing differentiated cells by inducing cell death, but poorly target slowly dividing cells, including cancer stem cells and dormant cancer cells, in the later course of treatment. Prolonged exposure to chemotherapy results in a decrease in the proportion of apoptotic cells in the tumour mass. To investigate and characterize the molecular basis of this phenomenon, microarray-based expression analysis was performed to compare tHcred2-DEVD-EGFP-caspase 3-sensor transfected C-26 tumour cells that were harvested after engraftment into mice treated with or without 5-FU. Peritoneal metastasis was induced by intraperitoneal injection of C-26 cells, which were subsequently reisolated from omental metastatic tumours after the mice were sacrificed by the end of the 10th day after tumour injection. The purity of reisolated tHcred2-DEVD-EGFP-caspase 3-sensor-expressing C-26 cells was confirmed using FLIM, and total RNA was extracted for gene expression profiling. The validation of relative transcript levels was carried out via real-time semiquantitative RT‒PCR assays. Our results demonstrated that chemotherapy induced the differential expression of mediators of cancer cell dormancy and cell survival-related genes and downregulation of both intrinsic and extrinsic apoptotic signalling pathways. Despite the fact that some differentially expressed genes, such as BMP7 and Prss11, have not been thoroughly studied in the context of chemoresistance thus far, they might be potential candidates for future studies on overcoming drug resistance.

Burkholderia pseudomallei (Bpm) is the causative agent of the disease melioidosis. As a facultative intracellular pathogen, Bpm has a complex lifestyle that culminates in cell-to-cell fusion and multinucleated giant cells (MNGCs) formation. The virulence factor responsible for MNGC formation is the type 6 secretion system (T6SS), a contractile nanomachine. MNGC formation is a cell-to-cell spread strategy that allows the bacteria to avoid the extracellular immune system and our previous data highlighted cell death, apoptosis, and inflammation as pathways significantly impacted by T6SS activity. Thusly, we investigated how the T6SS influences these phenotypes within the macrophage and pulmonary models of infection. Here we report that the T6SS is responsible for exacerbating apoptotic cell death during infection in both macrophages and the lungs of infected mice. We also demonstrate that although the T6SS does not influence differential macrophage polarization, the M2 polarization observed is potentially beneficial for Bpm pathogenesis and replication. Finally, we show that the T6SS contributes to the severity of inflammatory nodule formation in the lungs, which might be potentially connected to the amount of apoptosis that is triggered by the bacteria.

Infections of many viruses induce caspase activation to regulate multiple cellular pathways, including programmed cell death, immune signaling and etc. Characterizations of caspase cleavage sites and substrates are important for understanding the regulation mechanisms of caspase activation. Here, we identified and analyzed a novel caspase cleavage motif AEAD, and confirmed its caspase dependent cleavage activity in natural substrate, such as nitric oxide-associated protein 1 (NOA1). Fusing the enhanced green fluorescent protein (EGFP) with the mitochondrial marker protein Tom20 through the AEAD motif peptide localized EGFP to the mitochondria. Upon the activation of caspase triggered by Sendai virus (SeV) or herpes simplex virus type 1 (HSV-1) infection, EGFP diffusely localized to the cell due to the caspase-mediated cleavage, thus allowing visual detection of the virus-induced caspase activation. An AEAD peptide-derived inhibitor Z-AEAD-FMK were developed, which significantly inhibited the activities of caspases-1, -3, -6, -7, -8 and -9, exhibiting a broad caspase inhibition effect. The inhibitor further prevented caspases-mediated cleavage of downstream substrates, including BID, PARP1, LMNA, pro-IL-1β, pro-IL-18, GSDMD and GSDME, protecting cells from virus-induced apoptotic and pyroptotic cell death. Together, our findings provide a new perspective for the identification of novel caspase cleavage motifs and the development of new caspase inhibitors and anti-inflammatory drugs.

Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive target for the treatment of various malignancies; however, its therapeutic potential is limited because of the frequent occurrence of tumor cell resistance. In this study, we determined whether TRAIL resistance acquired by repeated administration could be overcome by HDAC inhibition in human colorectal cancer cells.

TRAIL-resistant HCT116 human colorectal cancer cells (HCT116-TR) were generated by repeated treatment with 10 and 25 ng/mL TRAIL twice weekly for 28 days.

The resulting TRAIL-resistant cells were noncross-resistant to other chemotherapeutic agents. The levels of histone acetylation-related proteins, such as ac-histone H4 and HDAC1, were altered in HCT116-TR cells compared with the parental HCT116 cell line. The combined treatment with TRAIL and HDAC inhibitors significantly increased apoptosis in HCT116-TR cells and indicated a synergistic effect. The mechanism by which HDAC inhibition sensitizes HCT116-TR cells to TRAIL is dependent on the intrinsic pathway. In addition, we found that HDAC inhibition enhanced the sensitivity of cells to TRAIL through mitogen-activated protein kinases/CCAAT/enhancer-binding protein homologs of protein-dependent upregulation of death receptor 5.

These results suggest that histone acetylation is responsible for acquired TRAIL resistance after repeated exposure and acquired resistance to TRAIL may be overcome by combination therapies with HDAC inhibitors.

Evading programmed cell death (PCD) is a hallmark of cancer that allows tumor cells to survive and proliferate unchecked. Endocytosis, the process by which cells internalize extracellular materials, has emerged as a key regulator of cell death pathways in cancer. Many tumor types exhibit dysregulated endocytic dynamics that fuel their metabolic demands, promote resistance to cytotoxic therapies, and facilitate immune evasion. This review examines the roles of endocytosis in apoptotic resistance and immune escape mechanisms utilized by cancer cells. We highlight how inhibiting endocytosis can sensitize malignant cells to therapeutic agents and restore susceptibility to PCD. Strategies to modulate endocytosis for enhanced cancer treatment are discussed, including targeting endocytic regulatory proteins, altering membrane biophysical properties, and inhibiting Rho-associated kinases. While promising, challenges remain regarding the specificity and selectivity of endocytosis-targeting agents. Nonetheless, harnessing endocytic pathways represents an attractive approach to overcome apoptotic resistance and could yield more effective therapies by rendering cancer cells vulnerable to PCD. Understanding the interplay between endocytosis and PCD regulation is crucial for developing novel anticancer strategies that selectively induce tumor cell death.

Programmed cell death via the both intrinsic and extrinsic pathways is regulated by interactions of the Bcl-2 family protein members that determine whether the cell commits to apoptosis via mitochondrial outer membrane permeabilization (MOMP). Recently the conserved C-terminal sequences (CTSs) that mediate localization of Bcl-2 family proteins to intracellular membranes, have been shown to have additional protein-protein binding functions that contribute to the functions of these proteins in regulating MOMP. Here we review the pivotal role of CTSs in Bcl-2 family interactions including: (1) homotypic interactions between the pro-apoptotic executioner proteins that cause MOMP, (2) heterotypic interactions between pro-apoptotic and anti-apoptotic proteins that prevent MOMP, and (3) heterotypic interactions between the pro-apoptotic executioner proteins and the pro-apoptotic direct activator proteins that promote MOMP.