Anlotinib synergizes with venetoclax to induce mitotic catastrophe in acute myeloid leukemia.

Venetoclax is a BCL2-targeted drug employed in treating various cancers, particularly hematologic malignancies. Venetoclax combination therapies are increasingly recognized as promising treatment strategies for acute myeloid leukemia (AML). In this study, we conducted an unbiased drug screen and identified anlotinib, a promising multi-targeted receptor tyrosine kinase inhibitor with oral activity currently utilized in the treatment of solid tumor, as a potent enhancer of venetoclax's anticancer activity in AML. Our investigation encompassed AML cell lines, primary cells, and mouse models, demonstrating effective low-dose combination therapy of anlotinib and venetoclax with minimal cytopenia or organ damage. Proteomic analysis revealed abnormal mitotic signals induced by this combination in AML cells. Mechanistically, anlotinib synergized with venetoclax by suppressing ARPP19 protein, leading to sustained activation of PP2A-B55δ. This inhibited AML cells from entering the mitotic phase, culminating in mitotic catastrophe and apoptosis. Additionally, we identified a specific synthetic lethal vulnerability in AML involving an ARPP19 mutation at S62 phosphorylation. These findings underscore the therapeutic potential of anlotinib and venetoclax combination therapy in AML, warranting further clinical investigation.

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

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

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

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

LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.

The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

Lipopolysaccharide delivery systems in innate immunity.

Lipopolysaccharide (LPS), a key component of the outer membrane in Gram-negative bacteria (GNB), is widely recognized for its crucial role in mammalian innate immunity and its link to mortality in intensive care units. While its recognition via the Toll-like receptor (TLR)-4 receptor on cell membranes is well established, the activation of the cytosolic receptor caspase-11 by LPS is now known to lead to inflammasome activation and subsequent induction of pyroptosis. Nevertheless, a fundamental question persists regarding the mechanism by which LPS enters host cells. Recent investigations have identified at least four primary pathways that can facilitate this process: bacterial outer membrane vesicles (OMVs); the spike (S) protein of SARS-CoV-2; host-secreted proteins; and host extracellular vesicles (EVs). These delivery systems provide new avenues for therapeutic interventions against sepsis and infectious diseases.

Diverse functions of cytochrome c in cell death and disease.

The redox-active protein cytochrome c is a highly positively charged hemoglobin that regulates cell fate decisions of life and death. Under normal physiological conditions, cytochrome c is localized in the mitochondrial intermembrane space, and its distribution can extend to the cytosol, nucleus, and extracellular space under specific pathological or stress-induced conditions. In the mitochondria, cytochrome c acts as an electron carrier in the electron transport chain, facilitating adenosine triphosphate synthesis, regulating cardiolipin peroxidation, and influencing reactive oxygen species dynamics. Upon cellular stress, it can be released into the cytosol, where it interacts with apoptotic peptidase activator 1 (APAF1) to form the apoptosome, initiating caspase-dependent apoptotic cell death. Additionally, following exposure to pro-apoptotic compounds, cytochrome c contributes to the survival of drug-tolerant persister cells. When translocated to the nucleus, it can induce chromatin condensation and disrupt nucleosome assembly. Upon its release into the extracellular space, cytochrome c may act as an immune mediator during cell death processes, highlighting its multifaceted role in cellular biology. In this review, we explore the diverse structural and functional aspects of cytochrome c in physiological and pathological responses. We summarize how posttranslational modifications of cytochrome c (e.g., phosphorylation, acetylation, tyrosine nitration, and oxidation), binding proteins (e.g., HIGD1A, CHCHD2, ITPR1, and nucleophosmin), and mutations (e.g., G41S, Y48H, and A51V) affect its function. Furthermore, we provide an overview of the latest advanced technologies utilized for detecting cytochrome c, along with potential therapeutic approaches related to this protein. These strategies hold tremendous promise in personalized health care, presenting opportunities for targeted interventions in a wide range of conditions, including neurodegenerative disorders, cardiovascular diseases, and cancer.

Targeting cuproplasia and cuproptosis in cancer.

Copper, an essential trace element that exists in oxidized and reduced forms, has pivotal roles in a variety of biological processes, including redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy and immune modulation; maintaining copper homeostasis is crucial as both its deficiency and its excess are deleterious. Dysregulated copper metabolism has a dual role in tumorigenesis and cancer therapy. Specifically, cuproplasia describes copper-dependent cell growth and proliferation, including hyperplasia, metaplasia and neoplasia, whereas cuproptosis refers to a mitochondrial pathway of cell death triggered by excessive copper exposure and subsequent proteotoxic stress (although complex interactions between cuproptosis and other cell death mechanisms, such as ferroptosis, are likely and remain enigmatic). In this Review, we summarize advances in our understanding of copper metabolism, the molecular machineries underlying cuproplasia and cuproptosis, and their potential targeting for cancer therapy. These new findings advance the rapidly expanding field of translational cancer research focused on metal compounds.

ATF4 in cellular stress, ferroptosis, and cancer.

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

A guideline on the molecular ecosystem regulating ferroptosis.

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

Targeting paraptosis in cancer: opportunities and challenges.

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

Adverse effects of ferroptotic therapy: mechanisms and management.

Ferroptosis, a nonapoptotic form of cell death characterized by iron accumulation and uncontrolled lipid peroxidation, holds promise as a therapeutic approach in cancer treatment, alongside established modalities, such as chemotherapy, immunotherapy, and radiotherapy. However, recent research has raised concerns about its side effects, including damage to immune cells, hematopoietic stem cells, liver, and kidneys, the development of cachexia, and the risk of secondary tumor formation. In this review, we provide an overview of these emerging findings, with a specific emphasis on elucidating the underlying mechanisms, and underscore the critical significance of effectively managing side effects associated with targeted ferroptosis-based therapy.

Gut Microbiome Mediates Ferroptosis Resistance for Colorectal Cancer Development.

Colorectal cancer is a prevalent cancer type in the United States, affecting both genders and influenced by genetics and environmental factors. The role of the gut microbiome in colorectal cancer development and therapy response is a burgeoning field of study. A recent study uncovered that trans-3-indoleacrylic acid (IDA), a microbial metabolite from P. anaerobius, promotes colorectal cancer by inhibiting ferroptosis, a type of nonapoptotic cell death driven by unrestricted lipid peroxidation and subsequent membrane damage. IDA activates aryl hydrocarbon receptor (AHR), a nuclear transcription factor, leading to the expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3). ALDH1A3, known for aldehyde detoxification, also contributes to ferroptosis resistance by generating reduced nicotinamide adenine dinucleotide (NADH), critical for the synthesis of reduced coenzyme Q10 (COQH10), by apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1). Knocking out AHR, AIFM2, or ALDH1A3 reverses the inhibitory effect of IDA on ferroptosis and IDA-mediated tumor growth. Significantly, P. anaerobius is enriched in patients with colorectal cancer, and supplementing IDA or P. anaerobius accelerates colorectal cancer progression in spontaneous or orthotopic mouse models. Taken together, these findings suggest that targeting P. anaerobius-mediated ferroptosis resistance emerges as a promising strategy to combat colorectal cancer development.

Ferroptosis in immunostimulation and immunosuppression.

Ferroptosis is a form of iron-dependent regulated cell death characterized by the accumulation of toxic lipid peroxides, particularly in the plasma membrane, leading to lytic cell death. While it plays a crucial role in maintaining the overall health and proper functioning of multicellular organisms, it can also contribute to tissue damage and pathological conditions. Although ferroptotic damage is generally recognized as an immunostimulatory process associated with the release of damage-associated molecular patterns (DAMPs), the occurrence of ferroptosis in immune cells or the release of immunosuppressive molecules can result in immune tolerance. Consequently, there is ongoing exploration of targeting the upstream signals or the machinery of ferroptosis to therapeutically enhance or inhibit the immune response. In addition to introducing the core molecular mechanisms of ferroptosis, we will focus on the immune characteristics of ferroptosis in pathological conditions, particularly in the context of infection, sterile inflammation, and tumor immunity.

The lipid basis of cell death and autophagy.

ABBREVIATIONS: ACSL: acyl-CoA synthetase long chain family; DISC: death-inducing signaling complex; DAMPs: danger/damage-associated molecular patterns; Dtgn: dispersed trans-Golgi network; FAR1: fatty acyl-CoA reductase 1; GPX4: glutathione peroxidase 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; LPS: lipopolysaccharide; MUFAs: monounsaturated fatty acids; MOMP: mitochondrial outer membrane permeabilization; MLKL, mixed lineage kinase domain like pseudokinase; oxPAPC: oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine; OxPCs: oxidized phosphatidylcholines; PUFAs: polyunsaturated fatty acids; POR: cytochrome p450 oxidoreductase; PUFAs: polyunsaturated fatty acids; RCD: regulated cell death; RIPK1: receptor interacting serine/threonine kinase 1; SPHK1: sphingosine kinase 1; SOAT1: sterol O-acyltransferase 1; SCP2: sterol carrier protein 2; SFAs: saturated fatty acids; SLC47A1: solute carrier family 47 member 1; SCD: stearoyl-CoA desaturase; VLCFA: very long chain fatty acids.

HMGB1 in the interplay between autophagy and apoptosis in cancer.

Lysosome-mediated autophagy and caspase-dependent apoptosis are dynamic processes that maintain cellular homeostasis, ensuring cell health and functionality. The intricate interplay and reciprocal regulation between autophagy and apoptosis are implicated in various human diseases, including cancer. High-mobility group box 1 (HMGB1), a nonhistone chromosomal protein, plays a pivotal role in coordinating autophagy and apoptosis levels during tumor initiation, progression, and therapy. The regulation of autophagy machinery and the apoptosis pathway by HMGB1 is influenced by various factors, including the protein's subcellular localization, oxidative state, and interactions with binding partners. In this narrative review, we provide a comprehensive overview of the structure and function of HMGB1, with a specific focus on the interplay between autophagic degradation and apoptotic death in tumorigenesis and cancer therapy. Gaining a comprehensive understanding of the significance of HMGB1 as a biomarker and its potential as a therapeutic target in tumor diseases is crucial for advancing our knowledge of cell survival and cell death.

TXNDC12 inhibits lipid peroxidation and ferroptosis.

Ferroptosis is a type of regulated cell death characterized by lipid peroxidation and subsequent damage to the plasma membrane. Here, we report a ferroptosis resistance mechanism involving the upregulation of TXNDC12, a thioredoxin domain-containing protein located in the endoplasmic reticulum. The inducible expression of TXNDC12 during ferroptosis in leukemia cells is inhibited by the knockdown of the transcription factor ATF4, rather than NFE2L2. Mechanistically, TXNDC12 acts to inhibit lipid peroxidation without affecting iron accumulation during ferroptosis. When TXNDC12 is overexpressed, it restores the sensitivity of ATF4-knockdown cells to ferroptosis. Moreover, TXNDC12 plays a GPX4-independent role in inhibiting lipid peroxidation. The absence of TXNDC12 enhances the tumor-suppressive effects of ferroptosis induction in both cell culture and animal models. Collectively, these findings demonstrate an endoplasmic reticulum-based anti-ferroptosis pathway in cancer cells with potential translational applications.

Cell type-specific induction of ferroptosis to boost antitumor immunity.

Traditional ferroptosis activators typically suppress antitumor immunity. Our discovery shows that N6F11, a small molecule compound, can selectively induce ferroptosis by targeting TRIM25-mediated GPX4 degradation in cancer cells while sparing immune cells. This breakthrough establishes a safe and effective strategy to enhance ferroptosis-driven antitumor immunity.

Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer.

Lipid peroxidation-dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) in cancer cells to trigger TRIM25-mediated K48-linked ubiquitination of GPX4, resulting in its proteasomal degradation. Functionally, N6F11 treatment caused ferroptotic cancer cell death that initiated HMGB1-dependent antitumor immunity mediated by CD8+ T cells. N6F11 also sensitized immune checkpoint blockade that targeted CD274/PD-L1 in advanced cancer models, including genetically engineered mouse models of pancreatic cancer driven by KRAS and TP53 mutations. These findings may establish a safe and efficient strategy to boost ferroptosis-driven antitumor immunity.