Trends in pharmacological sciences最新文献

Therapeutic hypothermia is robustly neuroprotective in models but slow to initiate and hard to sustain clinically. This gap motivates pharmacological strategies that capture 'cold' protection at normothermia. Recent advances across the cold-response landscape have made RNA layer mechanisms operational. These include temperature-gated alternative splicing coupled to nonsense-mediated decay and temperature-sensitive RNA secondary structure elements such as RNA G-quadruplexes (rG4) thermometers, which are now quantifiable and tractable. In this review, we present a development-oriented framework that spans membrane thermosensors, intracellular temperature decoders, and downstream cold effectors. We focus on RNA layer mechanisms while treating upstream non-RNA elements as contextual adjuncts. We outline an RNA-binding motif protein 3 (RBM3)-first translational roadmap mainly built on two orthogonal modalities: splice-switching antisense oligonucleotides and rG4-oriented chemotypes. Lastly, we define pharmacodynamic anchors, realistic clinical windows, and safety gates for early-phase testing of normothermic hypothermia mimetics.

Cuproptosis is a mitochondria- and copper-dependent regulated form of cell death that has attracted growing interest as a therapeutic strategy in oncology. Its core mechanism involves the aggregation of lipoylated proteins in the tricarboxylic acid cycle to trigger proteotoxic stress and the destabilization of iron-sulfur cluster proteins, leading to mitochondrial dysfunction. These two effects synergize to initiate this regulated form of cell death. Recent studies have expanded this framework, revealing multilayered regulation through the core proteins of cuproptosis, mitochondrial respiratory function, and cellular copper homeostasis. Translational efforts have led to the development of copper-based therapeutics, including ionophores and nanomaterials. The utilization of smart-responsive nanomaterials also offers improved precision in tumor delivery and resistance circumvention. Here, we provide an updated overview of the mechanisms and regulation of cuproptosis and critically evaluate therapeutic strategies targeting it for cancer treatment.

Idiopathic pulmonary fibrosis (IPF) is a progressive, age-associated interstitial lung disease with limited therapeutic options. Current antifibrotics modestly slow the decline but fail to halt or reverse fibrosis. Emerging evidence implicates two central hallmarks of aging-cellular senescence and impaired autophagy-in IPF pathogenesis. Senescent epithelial and stromal cells secrete proinflammatory and profibrotic mediators, while defective autophagic flux exacerbates protein and organelle accumulation, mitochondrial dysfunction, and maladaptive stress responses. Increasingly, these processes are recognized as reciprocally regulated, converging on signaling pathways such as transforming growth factor-β, adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin, nuclear factor kappa-light-chain enhancer of activated B cells, and reactive oxygen species. This review examines the senescence-autophagy axis, outlines conceptual frameworks to reconcile its paradoxical functions, and highlights emerging therapeutic strategies, including drug repurposing and next-generation interventions.

The complement system is a conserved network of plasma and membrane-associated proteins that supports immune defense and tissue homeostasis. In multiple sclerosis (MS), persistent complement activation contributes to neuroinflammation, demyelination, and axonal injury. However, the translation of complement-targeted therapies for MS treatment has been limited, largely due to uncertainty surrounding the complex and context-dependent roles of complement pathways within the central nervous system. This review integrates the latest preclinical and clinical insights to delineate pathogenic and reparative complement pathways and to support the stratification of MS phenotypes using complement biomarkers and signatures. We further review approved and emerging complement inhibitors with neurological relevance, focusing on their translational implications for MS. Together, this integrated framework may guide the rational design of future complement-targeted MS trials.

Once known only as immune sentinels, formyl peptide receptors (FPRs) have emerged as paradoxical regulators of ocular health, capable of driving injury or repair in a ligand-dependent manner. We discuss FPR signaling in diabetic retinopathy, dry eye disease, and retinitis pigmentosa, highlighting therapeutic opportunities arising from biased receptor modulation.

Drug resistance is a major challenge in cancer and infectious diseases, requiring innovative solutions. Recent research suggests that bacteria and cancer cells reprogram their metabolism and manipulate their external metabolic environment to resist a diverse range of therapeutics. Emerging technologies, including single-cell and spatial omics profiling, CRISPR chemogenomics, machine learning, and metabolic network modeling, have revealed the metabolic complexities within bacterial biofilms, tuberculosis granulomas, and the tumor microenvironment. Here, we examine metabolic mechanisms that aid drug resistance across these different disease areas; this includes activation of antioxidant defenses, manipulation of the host immune response, and rewiring of energy metabolism. This analysis of shared metabolic factors across diseases may inspire repurposing of drugs, immunotherapies, and dietary interventions to overcome resistance.

Nuclear liquid-liquid phase separation (LLPS) is now recognized as a fundamental mechanism that organizes transcription and DNA repair machinery into dynamic, membraneless condensates essential for genome integrity and gene regulation. Dysregulated LLPS has emerged as a key driver of oncogenesis; yet, how pathological condensates simultaneously fuel transcriptional addiction and genomic instability remains incompletely understood. Recent biophysical and molecular advances, particularly in multivalency, concentration thresholds, and condensate material states, have revealed that cancer-associated mutations rewire phase behavior to generate hyperstable yet fragile condensates. This review explores the role of aberrant nuclear LLPS in cancer pathogenesis and therapy resistance and uniquely proposes phase targeting through condensate fragility as a precision oncology strategy, distinguishing itself by integrating oncogenic mechanisms with actionable biophysical vulnerabilities rather than focusing solely on molecular inhibition.

Macrophages play pivotal roles in regulating immune responses during inflammation and cancer. Recent evidence indicates that macrophages are dynamic cells capable of switching between different functional states in response to stimuli from their local microenvironment. However, characterizing these functional states in the context of inflammation and cancer has been challenging due to a lack of powerful tools. To address this important issue, recent studies have employed single-cell technologies and emerging immunoinformatics methods to explore the relationship between macrophage phenotypic states and their cellular functions. Here, we synthesize insights from these studies and discuss the current understanding of macrophage diversity (heterogeneity) and adaptability (plasticity) in acute inflammation, chronic diseases, and cancer. We also highlight the molecular mechanisms that initiate macrophage state transitions during disease progression. By integrating knowledge gained from different disease models, we propose a conceptual framework for the future development of pharmacological approaches aimed at targeting macrophages effectively.

The neurovascular unit (NVU) is a multicellular system functioning to maintain healthy brain homeostasis and regulate the exchange of essential elements between the blood and the brain. Recent studies have shown that, in response to ischemic stroke (IS), the NVU undergoes dynamic structural remodeling and metabolic dysfunction, revealing new features of IS pathogenesis. Recent breakthroughs in single-cell multiomics provide emerging evidence regarding the spatiotemporal heterogeneity of NVU responses to IS. To date, clinical treatments for IS-induced brain injury remain very limited. These new studies have advanced our knowledge of the dynamic cellular and molecular changes of the NVU after IS, paving the way for new therapeutic strategies.