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Pyroptosis, apoptosis, and necroptosis are mainly programmed cell death (PCD) pathways for host defense and homeostasis. PANoptosis is a newly distinct inflammatory PCD pathway that is uniquely regulated by multifaceted PANoptosome complexes and highlights significant crosstalk and coordination among pyroptosis (P), apoptosis (A), and/or necroptosis(N). Although some studies have focused on the possible role of PANpoptosis in diseases, the pathogenesis of PANoptosis is complex and underestimated. Furthermore, the progress of PANoptosis and related agonists or inhibitors in disorders has not yet been thoroughly discussed. In this perspective, we provide perspectives on PANoptosome and PANoptosis in the context of diverse pathological conditions and human diseases. The treatment targeting on PANoptosis is also summarized. In conclusion, PANoptosis is involved in plenty of disorders including but not limited to microbial infections, cancers, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), ischemia-reperfusion, and organic failure. PANoptosis seems to be a double-edged sword in diverse conditions, as PANoptosis induces a negative impact on treatment and prognosis in disorders like COVID-19 and ALI/ARDS, while PANoptosis provides host protection from HSV1 or Francisella novicida infection, and kills cancer cells and suppresses tumor growth in colorectal cancer, adrenocortical carcinoma, and other cancers. Compounds and endogenous molecules focused on PANoptosis are promising therapeutic strategies, which can act on PANoptosomes-associated members to regulate PANoptosis. More researches on PANoptosis are needed to better understand the pathology of human conditions and develop better treatment.

γ-Aminobutyric acid (GABA) transporter 1 (GAT1) 1 regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating the levels of GABA in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy 2 . Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine 3 , with an ordered part of only 60 kDa. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter uptake. Our results provide insights into the mixed-type inhibition of GAT1 by tiagabine, which is an important anticonvulsant medication. Its pharmacodynamic profile, confirmed by our experimental data, suggests initial binding of tiagabine to the substrate-binding site in the outward-open conformation, whereas our structure presents the drug stalling the transporter in the inward-open conformation, consistent with a two-step mechanism of inhibition 4 . The presented structure of GAT1 gives crucial insights into the biology and pharmacology of this important neurotransmitter transporter and provides blueprints for the rational design of neuromodulators, as well as moving the boundaries of what is considered possible in single-particle cryo-electron microscopy of challenging membrane proteins. Structural determination of GAT1 using cryo-electron microscopy provides insights into the biology and pharmacology of this GABA transporter.

Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be sensitive to indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, indisulam induces rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlight a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrates metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour regression without relapse was observed in both xenograft and the Th- MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss, RNA splicing and metabolic changes confirmed in vivo. Our data show that dual-targeting of metabolism and RNA splicing with anticancer indisulam is a promising therapeutic approach for high-risk neuroblastoma. The prognosis of high-risk neuroblastoma is poor despite the availability of multimodal treatment. Here the authors show that high-risk neuroblastoma is sensitive to indisulam, a selective degrader of the splicing factor RBM39 through the dual targeting of RNA splicing and metabolism.

Key Points Heat shock protein 90 (HSP90) is a molecular chaperone of numerous oncoproteins. Therefore, cancer cells can be considered to be 'addicted' to this molecule. HSP90 is also a mediator of cellular homeostasis. As such, it facilitates numerous transient low-affinity protein–protein interactions that have only recently been identified using bioinformatic and proteomic techniques. Although primarily a cytoplasmic protein, HSP90 affects diverse nuclear processes, including transcription, chromatin remodelling and DNA damage-induced mutation. HSP90 is a conformationally dynamic protein. ATP binding to the amino (N) domain and its subsequent hydrolysis by HSP90 drive a conformational cycle that is essential for chaperone activity. In eukaryotes, co-chaperones and post-translational modifications regulate both client interactions with HSP90 and HSP90 ATPase activity. Co-chaperones and post-translational modifications can also affect the efficacy of HSP90 inhibitors. HSP90 inhibitors currently under clinical evaluation interact with the N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cycle, leading to client protein degradation. Because of the HSP90 client repertoire, HSP90 inhibitors may combat oncogene switching, which is an important mechanism of tumour escape from tyrosine kinase inhibitors. Derivatives of the coumarin antibiotic novobiocin represent an alternative strategy for inhibiting HSP90 by targeting a unique carboxy-terminal (C) domain. Optimal development of HSP90-directed therapeutics will depend on synthesizing information gained from careful genetic analysis of primary and metastatic tumours with an understanding of the unique environmental context in which the tumour is thriving at the expense of the host. Numerous oncoproteins depend on the molecular chaperone heat shock protein 90 (HSP90). However, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which the chaperone participates in both neoplastic and normal cellular physiology. The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90. However, although recent reports of the early clinical efficacy of HSP90 inhibitors are encouraging, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which HSP90 participates in both neoplastic and normal cellular physiology.

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity. A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease–causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat. Genet Med19 4, 430–438.

Key Points Promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARα) is a gain-of-function protein that represses RARα and non-RARα target genes and disrupts PML nuclear bodies. This results in immortal proliferation and the inhibition of terminal differentiation. Various clinical regimens combining retinoic acid (RA), arsenic trioxide and anthracyclines now definitively cure up to 90% of patients with acute promyelocytic leukaemia (APL). RA induces APL differentiation and transient remissions. Arsenic trioxide triggers both apoptosis and differentiation and, as a single agent, allows many APL cures. As initially shown in mouse models, their combination definitively cures most patients. Mechanistically, therapy-induced transcriptional activation (or derepression) is responsible for APL cell differentiation, and PML–RARα degradation by RA or arsenic trioxide results in APL eradication. Arsenic trioxide targets PML through oxidation-triggered disulphide bond formation and direct binding. This results in PML and PML–RARα sumoylation, ubiquitylation and proteasome-mediated degradation. Therapy-triggered oncoprotein degradation could be a generally applicable strategy to treat malignancies driven by fusion proteins or overactivation of transcription factors. This Review discusses the new data that have revealed surprising insights into the pathogenesis of acute promyelocytic leukaemia (APL) and the mechanism by which retinoic acid plus arsenic trioxide combination therapy targets the oncogenic fusion protein promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARα), curing most cases of APL. The fusion oncogene, promyelocytic leukaemia ( PML )–retinoic acid receptor-α ( RARA ), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML–RARα for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers.

EZH2 is a protein methyltransferase component of the polycomb repressive complex 2 (PRC2) that installs the H3K27me3 chromatin mark. EPZ005687 inhibits EZH2 function and H3K27 trimethylation in cells and selectively kills lymphoma cells that require EZH2 for proliferation. EZH2 catalyzes trimethylation of histone H3 lysine 27 (H3K27). Point mutations of EZH2 at Tyr641 and Ala677 occur in subpopulations of non-Hodgkin's lymphoma, where they drive H3K27 hypertrimethylation. Here we report the discovery of EPZ005687, a potent inhibitor of EZH2 ( K i of 24 nM). EPZ005687 has greater than 500-fold selectivity against 15 other protein methyltransferases and has 50-fold selectivity against the closely related enzyme EZH1. The compound reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. These data suggest that genetic alteration of EZH2 (for example, mutations at Tyr641 or Ala677) results in a critical dependency on enzymatic activity for proliferation (that is, the equivalent of oncogene addiction), thus portending the clinical use of EZH2 inhibitors for cancers in which EZH2 is genetically altered.

Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.

Key Points When bacteria become quiescent (that is, slow growing or non-growing), they can avoid being killed by bactericidal antibiotics. This phenomenon extends the period of morbidity experienced by the patient and necessitates prolonged antibiotic treatment to achieve a cure. The effects of such bacteria are evident from several infections that typically contain these organisms, such as biofilm diseases, osteomyeletis and tuberculosis granuloma. In the first decade of the new millenium, the discovery and development of antibiotics that target the function of the membrane have provided new paradigms with which to combat persisting bacteria. In one approach, agents disorganize the structure and function of the membrane bilayer, causing subsequent multiple antibacterial effects in cells. Many of these membrane-active agents are reported to kill bacterial biofilms. Moreover, agents that inhibit the function of bacterial respiratory and redox enzymes, thereby causing membrane depolarization and energy depletion, have been shown to kill dormant Mycobacterium tuberculosis . The effects of membrane-active agents on quiescent cell types arise from the fact that all living bacteria require an intact, functional membrane and all living cells require energy to sustain their viability, even without growth. Our understanding of slow-growing or non-growing bacteria has improved, as well as our knowledge about the mechanisms of membrane-acting agents. There are many opportunities for obtaining new classes of drugs based on our current understanding of the mechanisms behind these antimicrobials, as well as many challenges. Infections involving slow-growing and persistent bacteria, including Mycobacterium tuberculosis and biofilms, are difficult to treat. Here, Hurdle and colleagues argue that developing antibiotics to target the bacterial membrane and membrane functions is a promising approach for the treatment for these difficult-to-treat infections. Persistent infections involving slow-growing or non-growing bacteria are hard to treat with antibiotics that target biosynthetic processes in growing cells. Consequently, there is a need for antimicrobials that can treat infections containing dormant bacteria. In this Review, we discuss the emerging concept that disrupting the bacterial membrane bilayer or proteins that are integral to membrane function (including membrane potential and energy metabolism) in dormant bacteria is a strategy for treating persistent infections. The clinical applicability of these approaches is exemplified by the efficacy of lipoglycopeptides that damage bacterial membranes and of the diarylquinoline TMC207, which inhibits membrane-bound ATP synthase. Despite some drawbacks, membrane-active agents form an important new means of eradicating recalcitrant, non-growing bacteria.

Metronomic chemotherapy is the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. This type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms. The latest clinical trials of metronomic chemotherapy in adult and pediatric cancer patients are discussed and the authors highlight the research efforts that need to be made to facilitate the optimal development of metronomic chemotherapy in the clinic. Tumor angiogenesis is recognized as a major therapeutic target in the fight against cancer. The key involvement of angiogenesis in tumor growth and metastasis has started to redefine chemotherapy and new protocols have emerged. Metronomic chemotherapy, which is intended to prevent tumor angiogenesis, is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. The potential of metronomic chemotherapy was revealed in animal models a decade ago and the efficacy of this approach has been confirmed in the clinic. In the past 5 years, multiple clinical trials have investigated the safety and efficacy of metronomic chemotherapy in a variety of human cancers. While the results have been variable, clinical studies have shown that these new treatment protocols represent an interesting alternative for either primary systemic therapy or maintenance therapy. We review the latest clinical trials of metronomic chemotherapy in adult and pediatric cancer patients. Accumulating evidence suggests that the efficacy of such treatment may not only rely on anti-angiogenic activity. Potential new mechanisms of action, such as restoration of anticancer immune response and induction of tumor dormancy are discussed. Finally, we highlight the research efforts that need to be made to facilitate the optimal development of metronomic chemotherapy. Key Points Metronomic chemotherapy is based on the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks Metronomic chemotherapy was originally developed to overcome drug resistance by shifting the therapeutic target from tumor cells to the tumor vasculature In the past decade, several pilot and phase II clinical studies have established the potential efficacy and low toxicity of metronomic chemotherapy in adult and childhood cancer patients Metronomic chemotherapy combined with conventional chemotherapy, radiotherapy and/or targeted therapy is an emerging anti-cancer strategy Recent findings suggest that metronomic chemotherapy may be a multi-targeted cancer therapy rather than a simple anti-angiogenic therapy In addition to inhibiting tumor angiogenesis, metronomic chemotherapy might also restore anticancer immune response and induce tumor dormancy