Also published as: C Zeng, Cheng-Hui Zeng, Chu-Jie Zeng, Chuan-Chuan Zeng, F Zeng, Fantian Zeng, H Zeng, K Zeng, L Zeng, Leli Zeng, Liyao Zeng, Q Zeng, Q. Zeng, Qingmin Zeng, S Zeng, S. Zeng, SG Zeng, W.J. Zeng, X Zeng, Xianlu Zeng, Y Zeng, YY Zeng, Ye Zeng, You‐Liang Zeng, Yulan Zeng, Zhaolin Zeng, Zhaoyang Zeng
Mitochondrial outer membrane permeabilization (MOMP) refers to the increase in permeability of the mitochondrial outer membrane, allowing proteins, DNA, and other molecules to pass through the interme Show more
Mitochondrial outer membrane permeabilization (MOMP) refers to the increase in permeability of the mitochondrial outer membrane, allowing proteins, DNA, and other molecules to pass through the intermembrane space into the cytosol. As a crucial event in the induction of apoptosis, MOMP plays a significant role in regulating various forms of cell death, including apoptosis, ferroptosis, and pyroptosis. Importantly, MOMP is not a binary process of "all-or-nothing." Under sub-lethal stress stimuli, cells may experience a phenomenon referred to as minority MOMP (miMOMP), where only a subset of mitochondria undergo functional impairment, thereby disrupting the normal life cycle of the cell. This can lead to pathological and physiological changes such as tumor formation, cellular senescence, innate immune dysfunction, and chronic inflammation. This review focuses on the diversity of MOMP events to elucidate how varying degrees of MOMP under different stress conditions influence cell fate. Additionally, it summarizes the current research progress on novel antitumor therapeutic strategies targeting MOMP in clinical contexts. Show less
Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. Show more
Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, and regulating the balance between fatty acid and glucose oxidation. CRAT’s interplay with the mitochondrial carnitine shuttle, involving carnitine palmitoyltransferases (CPT1 and CPT2) and the carnitine carrier (SLC25A20), underscores its critical role in energy metabolism. Emerging evidence highlights the structural and functional diversity of CRAT and structurally related acetyltransferases across cellular compartments, illustrating their coordinated role in lipid metabolism, amino acid catabolism, and mitochondrial bioenergetics. Moreover, the structural insights into CRAT have paved the way for understanding its regulation and identifying potential modulators with therapeutic applications for diseases such as diabetes, mitochondrial disorders, and cancer. This review examines CRAT’s structural and functional aspects, its relationships with carnitine shuttle members and other carnitine acyltransferases, and its broader role in metabolic health and disease. The potential for targeting CRAT and its associated pathways offers promising avenues for therapeutic interventions aimed at restoring metabolic equilibrium and addressing metabolic dysfunction in disease states. Show less
Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite sig Show more
Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia-inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient-deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor-associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC. Show less
Biomolecular condensates exhibit distinct microenvironments that arise from interactions between proteins, RNA, and solutions. In aqueous solutions, these membraneless structures constantly encounter Show more
Biomolecular condensates exhibit distinct microenvironments that arise from interactions between proteins, RNA, and solutions. In aqueous solutions, these membraneless structures constantly encounter small molecules that could affect the structure and properties of the condensates. However, the effects of organic small molecules in water solutions on the microenvironments of condensates remain poorly understood. In this study, we used various organic solutes as an example to explore how small molecules could influence the physicochemical properties in the microenvironment of protein condensates. Particularly, we quantitatively studied micropolarity and microviscosity using a combination of techniques, including fluorescence lifetime imaging microscopy, fluorescence recovery after photobleaching, and passive rheology. Unexpectedly, our results revealed that the microenvironment was not correlated with the polarity of organic solutes; instead, the correlation was observed on the interaction strength between water and small molecules. We found that solutes with stronger interaction with water and weaker interaction with proteins increase the micropolarity and decrease the microviscosity of condensates. Furthermore, we demonstrated that the modulation of the micropolarity of condensates could impact the miscibility of multicomponent condensates. Finally, we showed that organic solutes could influence the micropolarity of condensates and the partitioning of products in condensates, thus affecting the rate and equilibrium of the chemical reactions. In summary, our work provides a quantitative analysis of how the microenvironment of biomolecular condensates is impacted by organic solutes. Since protein condensates coexist with various types of metabolites in the aqueous cellular milieu, results from this work offer insights into how organic metabolites could regulate the microenvironment and behaviors of biological condensates. Show less
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism t Show more
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Show less
Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the i Show more
Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases. Show less
AbstractUnderstanding the intricate molecular machinery that governs ferroptosis and leveraging this accumulating knowledge could facilitate disease prevention, diagnosis, treatment, and prognosis. Em Show more
AbstractUnderstanding the intricate molecular machinery that governs ferroptosis and leveraging this accumulating knowledge could facilitate disease prevention, diagnosis, treatment, and prognosis. Emerging approaches for the in situ detection of the major regulators and biological events across cellular, tissue, and in living subjects provide a multiscale perspective for studying ferroptosis. Furthermore, advanced applications that integrate ferroptosis detection and the latest technologies hold tremendous promise in ferroptosis research. In this review, we first briefly summarize the mechanisms and key regulators underlying ferroptosis. Ferroptosis detection approaches are then presented to delineate their design, mechanisms of action, and applications. Special interest is placed on advanced ferroptosis applications that integrate multifunctional platforms. Finally, we discuss the prospects and challenges of ferroptosis detection approaches and applications, with the aim of providing a roadmap for the theranostic development of a broad range of ferroptosis‐related diseases. Show less
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, Show more
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer. Show less
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less
Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington’s di Show more
Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington’s disease, and amyotrophic lateral sclerosis. Parthanatos is a multistep cell death pathway cascade that involves poly (ADP-ribose) polymerase 1 (PARP-1) overactivation, PAR accumulation, PAR binding to apoptosis-inducing factor (AIF), AIF release from the mitochondria, nuclear translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and MIF-mediated large-scale DNA fragmentation. All the key players in the parthanatos pathway are pleiotropic proteins with diverse functions. An in-depth understanding of the structure-based activity of the key factors, and the biochemical mechanisms of parthanatos, is crucial for the development of drugs and therapeutic strategies. In this review, we delve into the key players of the parthanatos pathway and reveal the multiple levels of therapeutic opportunities for treating parthanatos-based pathogenesis. Show less
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side Show more
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side effects. Much effort has been made to circumvent the drug resistance and general toxicity of these drugs. Among multifarious designs, monofunctional platinum(II) complexes with a general formula of [Pt(3A)Cl] + (A: Ammonia or amine) stand out as a class of “non-traditional” anticancer agents hopeful to overcome the defects of current platinum drugs. This review aims to summarize the development of monofunctional platinum(II) complexes in recent years. They are classified into four categories: fluorescent complexes, photoactive complexes, targeted complexes, and miscellaneous complexes. The intention behind the designs is either to visualize the cellular distribution, or to reduce the side effects, or to improve the tumor selectivity, or inhibit the cancer cells through non-DNA targets. The information provided by this review may inspire researchers to conceive more innovative complexes with potent efficacy to shake off the drawbacks of platinum anticancer drugs. Show less
Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss Show more
Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss-of-function mutations in ADAR p150 allow persistent activation of the interferon system by Alu dsRNAs and are causal for Aicardi-Goutières Syndrome. Heterodimers of ADAR and DICER1 regulate the switch from RNA- to protein-centric immunity. Loss of DICER1 function produces age-related macular degeneration, a different type of Alu-mediated disease. The overlap of Z-forming sites with those for the signal recognition particle likely limits invasion of primate genomes by Alu retrotransposons. Show less
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δ p or its potential component, Δ Ψ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δ p dissipation decreases superoxide formation dependent on Δ p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714. Show less
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence Show more
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less