Trends in pharmacological sciences最新文献

The bioenergetic crisis in cancer cachexia arises from early mitochondrial dysfunction that precipitates muscle wasting. In a recent study, Angelino et al. found that tumor-derived signals suppress the cAMP-protein kinase A (PKA)-CREB1 axis, destabilizing mitochondrial homeostasis. Restoring cAMP signaling through phosphodiesterase 4 (PDE4) inhibition rescued mitochondrial function, highlighting a promising strategy to mitigate tumor-induced cachexia.

The WEE-family kinases, WEE1 and PKMYT1, play critical roles in regulating the G2/M cell cycle checkpoint to maintain genomic stability. Cancer cells with DNA damage response (DDR) deficiencies become heavily reliant on WEE1 and PKMYT1 to avert mitotic catastrophe. This dependence creates a synthetic lethality vulnerability that offers a promising therapeutic strategy. While early WEE1 inhibitors faced challenges due to toxicity, next-generation highly selective agents are now advancing through clinical trials with improved safety and efficacy. Similarly, PKMYT1 inhibitors have emerged as a complementary approach, with several candidates under clinical evaluation. This review examines the evolving mechanistic basis of synthetic lethality, with emphasis on how targeted inhibition of WEE1 or PKMYT1 exploits DDR defects to selectively induce genomic instability in cancer cells. Furthermore, we highlight recent advances in selective WEE kinase inhibitors, discuss key challenges, and explore innovative strategies to accelerate their development.

Tumor cells often display distinct electrophysiological properties compared with normal cells, including more frequent ion channel dysregulation and pronounced membrane potential depolarization. These abnormalities give rise to irregular electrical activity and disrupted ion homeostasis, contributing to malignant phenotypes such as epithelial-mesenchymal transition (EMT), metabolic reprogramming, immune evasion, and chemoresistance. Given the pivotal role of ion channels in tumor biology, targeting ion channel dysregulation represents a promising therapeutic approach. This review highlights recent representative studies to shed light on the roles of various ion channel families - including potassium, sodium, calcium, chloride, and transient receptor potential channels - in tumor progression. Furthermore, it summarizes advances in the repurposing and development of ion channel modulators and discusses emerging external interference technologies that modulate tumor electrical activity as potential therapeutic approaches.

The optic nerve, a component of the central nervous system (CNS), comprises axons from retinal ganglion cells (RGCs) that exhibit limited regenerative capacity following injury. Recent advances have substantially deepened our understanding of the epigenetic mechanisms underlying RGC survival and axonal regeneration, encompassing DNA methylation, histone modifications, noncoding RNAs (ncRNAs), RNA methylation, and their complex interplay. Here, we review emerging research paradigms that underscore the potential of epigenetic modulation in RGC survival promotion and axonal regeneration. We further explore the dual roles of epigenetic interventions in enhancing regeneration via both RGC-intrinsic regenerative pathways and extracellular microenvironment remodeling. Moreover, we discuss recent clinical progress that underscores the translational promise of epigenetic strategies for precision diagnostics and targeted therapies in optic nerve repair.

Diabetic nephropathy (DN), a leading cause of chronic kidney disease and end-stage renal disease, remains a major clinical challenge. Current therapeutic strategies primarily delay rather than prevent disease progression, highlighting the urgent need for novel interventions. Emerging evidence implicates deubiquitinating enzymes (DUBs) in the dysregulation of key pathological processes in DN, including glycolipid metabolism, oxidative stress, inflammation, and fibrosis. By modulating the stability and activity of critical substrates, DUBs exert context-dependent dual roles in DN pathogenesis. This review summarizes current insights into the regulatory roles of DUBs in DN pathogenesis and discusses their potential as promising therapeutic targets for future clinical intervention.

Cataract and presbyopia are the leading causes of age-related vision impairment worldwide, yet non-surgical management options remain limited. Age-related changes in the lipid composition of the crystalline lens have been implicated in their pathophysiology, highlighting the lens lipidome as a potential therapeutic target. In this review we summarize how recent advances in high-resolution and spatial lipidomics have clarified age- and region-specific changes in the lens lipidome, and we evaluate recent research efforts to utilize topical lipid-replenishing formulations and lipid-modifying small molecules to reverse these changes. We outline challenges in drug delivery to the avascular and encapsulated lens, and highlight how emerging technologies such as nanoparticles may overcome barriers to lens penetration, providing a path toward a pharmacological lens intervention.

G protein-coupled receptors (GPCRs) regulate numerous pathophysiological processes and have traditionally been modulated at the orthosteric site. Targeting allosteric sites offers an alternative approach that can enhance selectivity, modulate signal bias, and reduce side effects. Photopharmacology enables precise spatial and temporal drug control of receptors by light using modified drug molecules incorporating chemical photoswitches, especially azobenzenes. Allosteric and dualsteric photoswitchable ligands, the latter targeting both orthosteric and allosteric sites, are being developed - to date mainly at metabotropic glutamate (mGlu), muscarinic acetylcholine (mACh or M), and cannabinoid (CB) receptors, since their allosteric sites have been described in the most detail and with the largest number of respective allosteric ligands developed. The novel ligands can photocontrol even more refined GPCR functions, like signal bias and degrees of partial agonism. This review describes the recent development for these GPCRs in allosteric and dualsteric photoswitchable ligands, highlighting the specific challenging design, which is even more complex than for orthosteric photoswitchable ligands, since structure-activity relationships (SARs) are steep and often insufficiently described, and spacer structures strongly influence binding.

Precision immunotherapy leverages the immune system to selectively eliminate abnormal cells while sparing healthy cells. Targeting specific peptide-human leukocyte antigen (pHLA) complexes, derived from cancer, autoimmune, and infectious disease, enables precise intervention, because these antigens are minimally expressed in normal tissues. However, designing binders with high specificity and low cross-reactivity remains challenging. Inspired by natural T cell receptor (TCR) recognition of pHLA complexes, synthetic approaches, including TCR-mimic antibodies (TCRm) and de novo pHLA binders, are emerging, adaptable into T cell engagers and adoptive therapies with promising specificity and efficacy. Moreover, advances in artificial intelligence (AI)-driven methods, immunopeptidomics, and computational protein design are accelerating the discovery and pan-allelic development of highly specific pHLA therapeutics. In this review, we discuss current approaches, mechanisms, preclinical and clinical data, and cutting-edge technologies shaping the future of pHLA-targeted immunotherapies.