Scientific disciplines routinely reassess methods but rarely the concepts guiding scientific reasoning. We identify three mechanisms of conceptual persistence: amnesia, institutionalisation, and reification—the process by which an operational construct is regarded as biological reality. These mechanisms may impede scientific self-correction, a challenge increasingly relevant as artificial intelligence learns from scientific literature.
How Lewy pathology forms and diversifies remains a central question in Parkinson's disease research. A recent study by Mahul-Mellier and Colleagues proposes a dynamic model in which inclusion maturation and organelle remodeling drive pathological heterogeneity, reshaping concepts of disease mechanisms and providing new perspectives on therapeutic approaches.
Tumor-intrinsic voltage-gated Cav3 calcium channels, comprising the Cav3.1, Cav3.2 and Cav3.3 isoforms, have been implicated in cancer cell proliferation and survival. Recent work by Dube et al. reveals a role for microenvironmental Cav3.2 channels in glioblastoma, promoting neuron-cancer cell crosstalk and identifying changes in immune-related programs associated with Cav3.2 deficiency.
Oncolytic viruses hold immense therapeutic promise but face formidable systemic delivery barriers. A new study by Xu et al. engineered immunoglobulin E-sensitized mast cells to selectively ferry these viruses into tumors. Excitingly, antigen-triggered degranulation precisely releases the viral payload and reshapes the immune microenvironment, offering a highly modular delivery paradigm.
Glioblastoma (GBM) remains a devastating disease for which standard temozolomide chemotherapy is limited by O6-methylguanine-DNA methyltransferase (MGMT)-mediated DNA damage repair. By targeting epidermal growth factor receptor (EGFR), a major oncogenic driver of GBM, Guo, Habib, and colleagues demonstrate that EGFR inhibition prior to temozolomide treatment induces an adaptive response that downregulates MGMT, enhancing therapeutic efficacy.
Pathological tau accumulation underlies a spectrum of neurodegenerative diseases collectively known as tauopathies. Although reducing tau remains the prevailing therapeutic strategy, indiscriminate tau reduction may compromise physiological functions and has demonstrated limited clinical efficacy. Growing evidence indicates disease- and stage-specific tau heterogeneity—spanning post-translational modifications (PTMs), aggregation states, and vulnerable cell populations—highlighting the necessity for improved targeting selectivity for pathological tau species. In this review, we discuss tau-targeting therapeutic modalities, including nucleic acids to suppress tau expression, immunotherapies and chimeric degraders to facilitate tau protein clearance, inhibitors of aggregation, and emerging strategies for tau PTM-editing and cellular-level interventions for neurofibrillary tangle-bearing neurons.
Pain remains a major clinical challenge because current analgesics lack spatiotemporal precision and frequently induce systemic adverse effects, tolerance, and dependence. Recent advances in photopharmacology have enabled reversible optical control of ion channels, G protein-coupled receptors, and neural circuits involved in nociceptive processing, providing new opportunities for precision analgesia. Progress in photoswitches, photocaged ligands, wireless optoelectronic systems, and nanodelivery platforms has substantially improved the in vivo applicability of light-responsive therapeutics. These developments have transformed photopharmacology from a mechanistic research tool into a potential translational strategy for pain treatment. In this review, we discuss how photopharmacological approaches are reshaping the investigation of peripheral and central pain signaling, highlight emerging light-controlled analgesics, and outline future directions toward clinically translatable, nonaddictive, and personalized pain therapeutics.
Lysosome-targeted protein degradation (LTPD) represents a therapeutic strategy that degrades membrane and extracellular target proteins through the endolysosomal pathway. LTPD chimeras are molecular degraders that mediate LTPD, but their in vivo performance is limited by poor spatiotemporal control of degradation—existing chimeras have suboptimal pharmacokinetics, tissue selectivity, and endolysosomal trafficking. To overcome these hurdles associated with chimeras, LTPD platforms have emerged. LTPD platforms function as chimera-loaded systems for targeted delivery and controlled release of chimeras, or as platform-based degraders that mediate disease-targeted and on-demand degradation without chimeras. We discuss how LTPD platforms spatiotemporally control degradation and describe their therapeutic applications. In particular, we summarize the design principles of LTPD platforms to address the stringent requirements imposed by the LTPD process. These principles may contribute to the rational design of LTPD platforms.
Recent studies identify amyloidogenic human amylin, secreted by the pancreas, as a potential link between type-2 diabetes and Alzheimer’s disease. Evidence suggests that pathogenic amylin signaling impairs cerebral bioenergetics, promoting tau hyperphosphorylation and neurodegeneration. Selective targeting of circulating amyloidogenic amylin and its pathogenic signaling may enable biomarker development and disease-modifying therapies.
Classic serotonergic psychedelics act primarily via 5-HT2A receptor agonism, yet their therapeutic effects and biological responses are heterogeneous. Biological sex remains an underexamined source of this variability because many clinical and preclinical studies have not been designed to test sex-by-treatment effects. Recent preclinical findings, together with more limited human evidence, suggest that sex and endocrine state can modulate serotonergic mechanisms relevant to psychedelic action, including 5-HT1A autoregulatory feedback, 5-HT2A signaling, serotonin clearance, neuroendocrine coupling, and neuroplastic cascades. This review synthesizes how sex- and state-sensitive serotonergic regulation may influence psychedelic signaling and outlines priorities for sex-informed translational research in preclinical and clinical settings.
Pharmacological targeting of Signal Transducer and Activator of Transcription 3 (STAT3) in cancer has demonstrable antitumor efficacy. However, suitably potent, efficacious, and safe STAT3 inhibitors are scarce, and only a handful have entered clinical trials, limiting our knowledge of the extent of clinical benefit. Outcomes of recently completed trials in advanced cancers range from improved overall survival and complete responses in a cohort of patients with phosphotyrosine STAT3 positivity to partial responses and progressive disease in unselected patients. Advancements in oligonucleotide technologies and the integration of E3 ligase-specific proteolysis-targeting chimeras and molecular glue protein degrader strategies are accelerating the transition of STAT3 inhibitors into clinical testing. This review examines recent STAT3-targeted modalities and their preclinical and clinical activities. It concludes by underscoring the value of biomarker-informed approaches to optimize patient outcomes, combination therapies to improve clinical benefits, and artificial intelligence/machine learning tools to accelerate development.
Per- and polyfluoroalkyl substances (PFAS) are persistent xenobiotics linked to neurodevelopmental, neurodegenerative, and neurological disorders. PFAS-induced gut microbiota remodelling may disrupt gut-brain signalling, thereby affecting brain functions and behaviour. Integrating microbiome endpoints (diversity, taxonomic shifts, and metabolic configuration) into PFAS research provides a framework to elucidate toxicodynamic mechanisms and to inform the development of targeted, mechanism-based therapeutic strategies.
The clinical translation of stimulator of interferon genes (STING)agonist-based cancer immunotherapy is limited by uncontrolled and sustained STING activation, which leads to immune exhaustion and systemic toxicity. In this forum, we critically analyze recent advances, including stimuli-responsive, biomimetic, pulsatile, intracellular-triggered release, and synergistic systems that enable precise spatiotemporal STING activation, as well as associated gaps in clinical translation. Finally, we present futuristic perspectives on next-generation STING-based cancer immunotherapy strategies.
The complement system is essential for distinguishing self-tissue from foreign threats; however, complement activation on biomedical surfaces such as implants, transplants, or drug-delivery systems may lead to severe thromboinflammatory complications. Unlike systemic complement inhibitors, surface-targeted strategies remain scarce, despite their potential advantages regarding safety and efficacy. Recent years have seen the emergence of diverse surface-targeting approaches that impair different mechanisms underlying complement-mediated complications. These strategies, ranging from surface coatings to inhibitors targeting complement-tagged surfaces, are progressing from conceptual development to clinical application. In this review, we provide a comprehensive overview of complement-activation mechanisms on biomedical surfaces, highlight ongoing clinical investigations, and discuss a broad spectrum of emerging approaches to prevent adverse complement activation on biomedical interfaces.
Molecular chaperones play a central role in kinase homeostasis by guiding the folding, maturation, and stability of kinase clients. Yet advances in kinase folding and post-translational modification have not been adequately integrated into a coherent chaperone-centered framework, limiting a unified understanding of kinase homeostasis, and constraining more systematic efforts to target the chaperone-kinase axis. Recent structural and mechanistic studies now support a model in which chaperone assemblies function as regulatory platforms that coordinate kinase maturation, modification, and fate control. This review integrates these advances into a chaperone-centered view of kinase homeostasis and discusses pharmacological strategies targeting the chaperone-kinase axis, including chaperone modulation, interface disruption, and bifunctional approaches.
