Artificial intelligence (AI) has progressed from experimental curiosity to clinical utility, with AI-designed therapeutics now in human trials across diverse therapeutic areas. This review critically compares 5 leading AI-driven discovery platforms: generative chemistry, phenomics-first systems, integrated target-to-design pipelines, knowledge-graph repurposing, and physics-plus-machine learning design. Key developments since 2024 include positive phase IIa results for Insilico Medicine's Traf2- and Nck-interacting kinase inhibitor, ISM001-055, in idiopathic pulmonary fibrosis. Another key development was the Recursion-Exscientia merger, which integrated phenomic screening with automated precision chemistry into a full end-to-end platform. In addition, advancement of the Nimbus-originated tyrosine kinase 2 inhibitor, zasocitinib (TAK-279), into phase III clinical trials exemplifies Schrödinger's physics-enabled design strategy reaching late-stage clinical testing. Emerging platforms such as Insitro, Isomorphic Labs, Atomwise, and XtalPi illustrate the field's expanding geographic and technical footprint. SIGNIFICANCE STATEMENT: Artificial intelligence (AI) is reshaping pharmacology by shortening discovery timelines, potentially reducing attrition, and expanding the design space of therapeutic candidates. Alongside technical milestones, regulatory and ethical frameworks from the US Food and Drug Administration and European Medicines Agency are beginning to address transparency, bias, accountability, intellectual property, and data privacy. Robotics tightly integrated with AI now enables self-driving laboratories that accelerate design-make-test-learn cycles and improve reproducibility. Together, these advances chart a forward-looking roadmap in which multimodal foundation models, robotics-led platforms, and hybrid physics-AI strategies are poised to accelerate translation, derisk development, and establish trustworthy AI as a cornerstone of modern drug discovery.

Antimicrobial resistance represents one of the most pressing global health challenges of the 21st century, significantly compromising the efficacy of conventional antibiotics. In response to this crisis, the World Health Organization has updated its 2024 list of priority bacterial pathogens-classified into critical-, high-, and medium-risk groups-based on their resistance mechanisms, clinical impact, and global dissemination. This comprehensive review explores the emerging therapeutic potential of antimicrobial peptides (AMPs) when used in synergistic combinations with conventional antibiotics. By dissecting the mechanistic interplay-ranging from membrane disruption and efflux pump inhibition to biofilm penetration and intracellular antibiotic delivery-we provide a structured analysis of how these dual strategies overcome specific resistance barriers. Special emphasis is given to the World Health Organization-designated pathogens such as Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-resistant/vancomycin-resistant), Enterococcus faecium, Salmonella spp., Shigella spp., and Mycobacterium tuberculosis. Supported by extensive in vitro and in vivo data, this review catalogs dozens of successful AMP-antibiotic pairings, highlighting their fractional inhibitory concentration indices, clinical relevance, and implications for translational development. The evidence presented demonstrates that AMPs not only potentiate antibiotic action but also extend the useful lifespan of existing drugs while reducing toxicity. These findings support the advancement of AMP-based combination therapies as a next-generation strategy to contain resistance and restore the effectiveness of the antimicrobial arsenal. SIGNIFICANCE STATEMENT: Antimicrobial resistance remains a global health emergency, especially among World Health Organization 2024 priority pathogens. This review highlights the therapeutic promise of synergistic combinations between antimicrobial peptides and conventional antibiotics, offering a rational strategy to restore efficacy, overcome resistance mechanisms, and extend the clinical utility of existing drugs. By bridging microbiology, pharmacology, and translational medicine, this work provides timely insights for researchers and policymakers seeking innovative solutions to combat multidrug-resistant infections.

Neurological diseases often lead to life-altering consequences, underscoring the urgent need for therapies that can reverse or mitigate their effects. Effective management of neurological disorders necessitates a thorough understanding of the common pathological mechanisms driving their onset and progression. Mitochondrial dysfunction and oxidative stress stand out as critical contributors to neuronal damage, implicated in traumatic brain injury, stroke, and amyotrophic lateral sclerosis. Disruptions in energy metabolism lead to the accumulation of reactive oxygen species and elevate the level of neural injury. Moreover, these imbalances disrupt cellular homeostasis and activate apoptotic pathways, further exacerbating neuronal loss and ultimately worsening the clinical prognosis. In this context, edaravone (Eda), a Food and Drug Administration-approved free radical scavenger, has emerged as a compelling candidate for the treatment of neuropathologies. This review provides a comprehensive overview of Eda, detailing its chemical structure and pharmacokinetic profile, with a focus on strategies to enhance its delivery to the central nervous system by modulating blood-brain barrier permeability or employing delivery systems that facilitate central nervous system penetration. Moreover, the review examines Eda's pharmacodynamic properties, including the signaling pathways it influences. The neurotherapeutic potential of Eda is further examined through in vitro and in vivo models of neurological disease. Insights from clinical trials are discussed to bridge the gap between preclinical findings and patient outcomes. Finally, the review highlights the synergistic effects of combining Eda with other pharmacological agents or therapeutic interventions, underscoring its promise as a versatile and indispensable treatment for neurological disorders. SIGNIFICANCE STATEMENT: Edaravone, a Food and Drug Administration-approved free radical scavenger, shows broad neuroprotective potential by mitigating oxidative stress and mitochondrial dysfunction across diverse neurological disorders, including stroke, amyotrophic lateral sclerosis, and traumatic brain injury. By synthesizing preclinical and clinical evidence, this review highlights edaravone's pleiotropic therapeutic actions, identifies translational challenges, and underscores its promise as a versatile treatment strategy for neurodegenerative and acute and chronic brain conditions.

Sleep disturbance is increasingly recognized as a viable prevention target that could lower dementia risk. While a wide range of pharmacological options exist to manage sleep disturbance in people living with dementia, their use often does not adherent to the quality use of medicine. The complex nature of dementia as a syndrome often requires drugs that target multiple complaints (eg, sleep, cognition, and mood) and thus could produce psychological and physiological side effects that have the potential to do more harm than confer benefits. Therefore, this review first provides an expert narration of the pharmacology of sleep and the mechanisms of agents used to treat sleep disturbance. Then, a systematic scoping review was conducted to analyze evidence from studies over the past 10 years, which examined various pharmacological agents used for sleep disturbance in people living with dementia. SIGNIFICANCE STATEMENT: Sleep disturbances are a common consequence of the neurodegenerative changes occurring in dementia syndromes. They may also be etiologically linked to its development and progression. This review summarizes the pharmacological basis of sleep and collates the impact of medications used for dementia or sedatives on sleep and cognition outcomes. The review highlights gaps in research and will provide clinicians with key information required to make decisions about the quality use of medications to improve sleep health in those with dementia.

Carbon dots (CDs), a remarkable class of novel nanomaterials, have attracted significant attention in the biomedical field owing to their extraordinary chemical, physical, and biological properties. Among their diverse applications, CDs stand out as highly promising nanocarriers for drug delivery owing to their ability to cross cell membranes efficiently and deliver therapeutic agents directly to damaged cells or tissues. What makes CDs truly unique is their intrinsic photoluminescence and the abundance of reactive groups on their surface, allowing for extensive multifunctionalization. This versatility enables the conjugation of various functional groups, therapeutic molecules, biomolecules, and targeting ligands, paving the way for an integrated approach to diagnosis and therapy. This review highlights the latest advancements in the application of CDs for drug delivery, focusing on their use in anticancer and antiviral therapies, as well as in the treatment of osteoarticular diseases and neurological disorders. Particular attention is given to the critical aspects of biocompatibility and toxicity, which remain key challenges for their translation into clinical practice. These promising developments position CDs as cutting-edge tools in nanopharmacology, offering exciting opportunities for future therapeutic innovations. SIGNIFICANCE STATEMENT: Carbon dots represent a transformative class of nanomaterials whose tunable chemistry, intrinsic photoluminescence, and high biocompatibility make them highly promising for next-generation drug delivery. By enabling targeted, multifunctional, and trackable therapeutic strategies across cancer, viral infections, osteoarticular, and neurological diseases, carbon dots offer a unique platform that bridges diagnostics and therapy, with the potential to significantly advance precision medicine while addressing current limitations of conventional drug carriers.

The endoplasmic reticulum (ER) is a dynamic membranous organelle that accounts for nearly half of the total membrane content in hepatocytes and serves as a central hub for protein folding and lipid biosynthesis. Given the liver's essential functions in protein production and secretion, lipid handling, and xenobiotic metabolism, hepatocyte ER homeostasis is essential for systemic metabolic control and health. Metabolic dysfunction-associated steatotic liver disease, which affects nearly 30% of the global population, is strongly linked to hepatic ER stress. Accumulating evidence highlights the unfolded protein response (UPR) as a key mechanistic regulator that integrates proteostasis and metabolic stress, thereby influencing disease progression from simple steatosis to inflammation-driven metabolic dysfunction-associated steatohepatitis (MASH). More recently, ER stress has also been implicated as a driver of MASH-related hepatocellular carcinoma, the most common primary liver cancer. In this review, we provide a comprehensive overview of the dynamic roles of the UPR and ER stress in hepatocytes, with particular emphasis on mechanistic insights derived from murine models of MASH-related hepatocellular carcinoma. We also summarize the current animal models of MASH that depend on hepatic ER stress. Finally, we discuss therapeutic candidates for MASH treatment, whose mechanisms of action involve ER stress and the UPR. SIGNIFICANCE STATEMENT: The endoplasmic reticulum (ER) functions as a central signaling hub, transmitting stress cues to transcriptional and translational programs through activation of the unfolded protein response, which orchestrates adaptive responses required for stress recovery. Given that hepatocytes are the largest cell population responsible for systemic protein distribution through ER-regulated protein synthesis, precise control of hepatic ER stress is essential not only for maintaining normal hepatocyte function but also for developing therapeutic strategies against ER stress-driven metabolic dysfunction-associated steatotic liver disease.

γ-Hydroxybutyrate (GHB) is a multifaceted compound with an intriguing, yet undeciphered, pharmacology in the mammalian brain. As a metabolite of GABA it is tightly regulated in terms of synthesis and degradation, and is found in micromolar concentrations in the brain. When GHB is taken in high pharmacological doses, it causes euphoria, relaxation, hypothermia, and sedation, and regulates sleep. Through careful pharmacological and genetic studies, this profile has been convincingly matched to the metabotropic GABAB receptor where GHB is a weak agonist. These effects explain the illicit substance use of GHB, but also its clinically useful effects as a drug in alcoholism and narcolepsy. Additionally, GHB binds with high affinity to a discrete binding site with high expression in the forebrain, and with very well defined anatomical, biochemical, and pharmacological characteristics. Despite this clear profile, the molecular identity of this binding protein or alleged "GHB receptor" has remained uncertain. However, recently, prompted by the development of GHB analogs with low nanomolar affinity and selectivity for the high-affinity site, the target was revealed to be the Ca2+/calmodulin (CaM)-dependent protein kinase II alpha subunit-a highly important brain kinase, mediating both physiological processes in synaptic plasticity, and detrimental Ca2+ signaling and cell death in cases of brain ischemia. The discovery of calmodulin-dependent protein kinase II alpha subunit as the high-affinity brain target for GHB represents a major leap forward in our understanding of GHB neurobiology, and dictates new times for GHB research, suggesting a potential role for GHB and GHB analogs as integrators of inhibitory and excitatory brain signaling. SIGNIFICANCE STATEMENT: γ-Hydroxybutyrate is a molecule with a multitude of actions in the mammalian brain, and with a rather complex molecular pharmacology. A low affinity at GABAB receptors, located mainly at inhibitory synapses, and a high affinity at the Ca2+/CaM-dependent protein kinase II alpha subunit, located at excitatory synapses, makes GHB pharmacology especially intriguing.

We aimed to review clinical research on the safety profiles of antidepressant drugs and associations with maternal depression and neonatal outcomes. We focused on neuroendocrine changes during pregnancy and their effects on antidepressant pharmacokinetics. Pregnancy-induced alterations in drug disposition and metabolism impacting mothers and their fetuses are discussed. We considered evidence for the risks of antidepressant use during pregnancy. Teratogenicity associated with ongoing treatment, new prescriptions during pregnancy, or pausing medication while pregnant was examined. The Food and Drug Administration advises caution regarding prenatal exposure to most drugs, including antidepressants, largely owing to a dearth of safety studies caused by the common exclusion of pregnant individuals in clinical trials. We contrasted findings on antidepressant use with the lack of treatment where detrimental effects to mothers and children are well researched. Overall, drug classes such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors appear to have limited adverse effects on fetal health and child development. In the face of an increasing prevalence of major mood and anxiety disorders, we assert that individuals should be counseled before and during pregnancy about the risks and benefits of antidepressant treatment given that withholding treatment has possible negative outcomes. Moreover, newer therapeutics, such as ketamine and κ-opioid receptor antagonists, warrant further investigation for use during pregnancy. SIGNIFICANCE STATEMENT: The safety of antidepressant use during pregnancy remains controversial owing to an incomplete understanding of how drug exposure affects fetal development, brain maturation, and behavior in offspring. This leaves pregnant people especially vulnerable, as pregnancy can be a highly stressful experience for many individuals, with stress being the biggest known risk factor for developing a mood or anxiety disorder. This review focuses on perinatal pharmacotherapy for treating mood and anxiety disorders, highlighting the current knowledge and gaps in our understanding of consequences of treatment.

Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated cell growth. Genetic mutations can determine tumor onset by either augmenting cell division rates or restraining normal controls such as cell cycle arrest or apoptosis. As a result, tumor cells not only undergo uncontrolled cell division but also become compromised in their ability to exit the cell cycle accurately. Regulation of cell cycle progression is enabled by specific surveillance mechanisms known as cell cycle checkpoints, and aberrations in these signaling pathways often culminate in cancer. For instance, DNA damage checkpoints, which preclude the generation and augmentation of DNA damage in the G1, S, and G2 cell cycle phases, are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Notably, tumors have evolved to become dependent on checkpoints for their survival. For example, checkpoint pathways such as the DNA replication stress checkpoint and the mitotic checkpoint rarely undergo mutations and remain intact because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation leading to cell death. In this review, we initially focus on cell cycle control pathways and specific functions of checkpoint signaling involved in normal and cancer cells and then proceed to examine how cell cycle control and checkpoint mechanisms can provide new therapeutic windows that can be exploited for cancer therapy. SIGNIFICANCE STATEMENT: DNA damage checkpoints are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Conversely, DNA replication stress and mitotic checkpoints rarely undergo mutations because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation, leading to cancer cell death. This review focuses on the checkpoint signaling mechanisms involved in cancer cells and how an emerging understanding of these pathways can provide new therapeutic opportunities for cancer therapy.