Liyan Jia, Yan Qiao · 2025 · Journal of the American Chemical Society · ACS Publications · added 2026-04-20
In nature, life is inherently dissipative. Cells continuously consume energy (such as ATP) to sustain homeostasis, drive metabolism, and respond dynamically to environmental cues. Inspired by this pri Show more
In nature, life is inherently dissipative. Cells continuously consume energy (such as ATP) to sustain homeostasis, drive metabolism, and respond dynamically to environmental cues. Inspired by this principle, we develop a synthetic protocell system that exhibits dissipative behavior and initiates metabolic-like processes. Our design features synthetic vesicles formed from a cationic surfactant, which undergo a fuel-driven transformation into coacervate protocells via liquid-liquid phase separation. Dissipation is achieved through alkaline phosphatase (ALP)-catalyzed ATP hydrolysis, driving the reverse transition from coacervates back to vesicles. The distinct physicochemical properties and internal organization of vesicle and coacervate protocells enable us to design functional regulators capable of producing secondary signals, such as fluorescence and enzymatic products. This work offers a strategy for engineering enzymatic reaction-regulated dissipative behaviors of protocell systems that emulate key aspects of cellular metabolism, representing a step toward synthetic life-like systems with dynamic behavior and functional complexity. 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
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
The Zα domain has a compact α/β architecture containing a three-helix bundle flanked on one side by a twisted antiparallel β sheet. This domain displays a specific affinity for double-stranded nucleic Show more
The Zα domain has a compact α/β architecture containing a three-helix bundle flanked on one side by a twisted antiparallel β sheet. This domain displays a specific affinity for double-stranded nucleic acids that adopt a left-handed helical conformation. Currently, only three Zα-domain proteins have been identified in eukaryotes, specifically ADAR1, ZBP1, and PKZ. ADAR1 is a double-stranded RNA (dsRNA) binding protein that catalyzes the conversion of adenosine residues to inosine, resulting in changes in RNA structure, function, and expression. In addition to its editing function, ADAR1 has been shown to play a role in antiviral defense, gene regulation, and cellular differentiation. Dysregulation of ADAR1 expression and activity has been associated with various disease states, including cancer, autoimmune disorders, and neurological disorders. As a sensing molecule, ZBP1 exhibits the ability to recognize nucleic acids with a left-handed conformation. ZBP1 harbors a RIP homotypic interaction motif (RHIM), composed of a highly charged surface region and a leucine-rich hydrophobic core, enabling the formation of homotypic interactions between proteins with similar structure. Upon activation, ZBP1 initiates a downstream signaling cascade leading to programmed cell death, a process mediated by RIPK3 via the RHIM motif. PKZ was identified in fish, and contains two Zα domains at the N-terminus. PKZ is essential for normal growth and development and may contribute to the regulation of immune system function in fish. Interestingly, some pathogenic microorganisms also encode Zα domain proteins, such as, Vaccinia virus and Cyprinid Herpesvirus. Zα domain proteins derived from pathogenic microorganisms have been demonstrated to be pivotal contributors in impeding the host immune response and promoting virus replication and spread. This review focuses on the mammalian Zα domain proteins: ADAR1 and ZBP1, and thoroughly elucidates their functions in the immune response. Show less
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potenti Show more
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potential side-effects. Bioinformatic approaches, advances in machine learning techniques and the increasing deposition of high-throughput data in public databases have significantly contributed to recent advances in the field, but it is not straightforward to decide which data and methods are most suitable to use in a given case. In this review, we focus on these methods and data and their applications in generating MoA hypotheses for subsequent experimental validation. We discuss compound-specific data such as -omics, cell morphology and bioactivity data, as well as commonly used supplementary prior knowledge such as network and pathway data, and provide information on databases where this data can be accessed. In terms of methodologies, we discuss both well-established methods (connectivity mapping, pathway enrichment) as well as more developing methods (neural networks and multi-omics integration). Finally, we review case studies where the MoA of a compound was successfully suggested from computational analysis by incorporating multiple data modalities and/or methodologies. Our aim for this review is to provide researchers with insights into the benefits and drawbacks of both the data and methods in terms of level of understanding, biases and interpretation – and to highlight future avenues of investigation which we foresee will improve the field of MoA elucidation, including greater public access to -omics data and methodologies which are capable of data integration. Show less
Simple Summary The gene-regulatory factors ATF5, CEBPB and CEBPD promote survival, growth, metastasis and treatment resistance of a range of cancer cell types. Presently, no drugs target all three at Show more
Simple Summary The gene-regulatory factors ATF5, CEBPB and CEBPD promote survival, growth, metastasis and treatment resistance of a range of cancer cell types. Presently, no drugs target all three at once. Here, with the aim of treating cancers, we designed novel cell-penetrating peptides that interact with and inactivate all three. The peptides Bpep and Dpep kill a range of cancer cell types in culture and in animals. In animals with tumors, they also significantly increase survival time. In contrast, they do not affect survival of non-cancer cells and have no apparent side effects in animals. The peptides work in combination with other anti-cancer treatments. Mechanism studies of how the peptides kill cancer cells indicate a decrease in survival proteins and increase in death proteins. These studies support the potential of Bpep and Dpep as novel, safe agents for the treatment of a variety of cancer types, both as mono- and combination therapies. Abstract Transcription factors are key players underlying cancer formation, growth, survival, metastasis and treatment resistance, yet few drugs exist to directly target them. Here, we characterized the in vitro and in vivo anti-cancer efficacy of novel synthetic cell-penetrating peptides (Bpep and Dpep) designed to interfere with the formation of active leucine-zipper-based dimers by CEBPB and CEBPD, transcription factors implicated in multiple malignancies. Both peptides similarly promoted apoptosis of multiple tumor lines of varying origins, without such effects on non-transformed cells. Combined with other treatments (radiation, Taxol, chloroquine, doxorubicin), the peptides acted additively to synergistically and were fully active on Taxol-resistant cells. The peptides suppressed expression of known direct CEBPB/CEBPD targets IL6 , IL8 and asparagine synthetase ( ASNS ), supporting their inhibition of transcriptional activation. Mechanisms by which the peptides trigger apoptosis included depletion of pro-survival survivin and a required elevation of pro-apoptotic BMF. Bpep and Dpep significantly slowed tumor growth in mouse models without evident side effects. Dpep significantly prolonged survival in xenograft models. These findings indicate the efficacy and potential of Bpep and Dpep as novel agents to treat a variety of cancers as mono- or combination therapies. 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
The condensation of DNA is essential for biological processes such as DNA transcription and replication, and its study receives additional impetus from an interest in gene therapy. Although many effic Show more
The condensation of DNA is essential for biological processes such as DNA transcription and replication, and its study receives additional impetus from an interest in gene therapy. Although many efficacious condensing agents have been discovered and investigated, little is known about the conversation of condensation-release under suitable conditions. A novel class of DNA condensing agents based on small azaheterocyclic metal-binding molecules has been discovered and described. Both linear and plasmid DNA can be condensed to nanoparticles by the title compounds with 50 °C incubation, especially in the presence of divalent metal ions. Importantly, this condensation may be released to original forms with little or no damage to the DNA under incubation at physiological temperatures. These changes in DNA morphology over time have been analyzed by gel electrophoresis, circular dichroism (CD), and atomic force microscopy (AFM). The present work might help to develop strategies for the design and synthesis of controllable condensing agents, which may also be applied to control gene expression and delivery. Show less