Heart failure (HF) poses a substantial challenge to healthcare systems globally, particularly at the advanced stages of various cardiac diseases, due to its high morbidity and mortality rates. This study aimed to assess the therapeutic potential of artesunate in a mouse model of HF induced by isoprenaline. Adult male C57BL/6J mice were subcutaneously injected with isoprenaline (50 mg/kg/day) for 14 consecutive days, with artesunate administered during the last 7 days. Strikingly, late-phase intervention with artesunate retarded the decline of cardiac function and attenuated lung congestion in HF mice. Although it did not ameliorate cardiac hypertrophy, as indicated by unchanged heart weight and myocyte cross-sectional area, artesunate markedly alleviated interstitial fibrosis and downregulated mRNA expression of Tgfb1 and Col1a1 in failing hearts. Mechanistically, artesunate suppressed myocardial infiltration of monocytes/macrophages and downregulated key inflammatory genes, including Ccl2, Il6, Nos2, Il1b, and Tnf. Furthermore, it elevated protein levels of Nrf2, glutathione peroxidase 4, and heme oxygenase-1, and suppressed ferroptosis in failing hearts. In summary, late-phase intervention with artesunate slows HF progression in mice by mitigating myocardial inflammation, fibrosis, and ferroptosis, independent of hypertrophy regression. SIGNIFICANCE STATEMENT: Although late-phase intervention with artesunate does not impact cardiac hypertrophy, it reduces myocardial inflammation and fibrosis, slowing heart failure progression. Our findings provide compelling evidence for artesunate as a promising therapeutic candidate, with its efficacy in a clinically relevant experimental context underscoring its significant translational potential.

Low-density lipoprotein receptor-related protein-1 (LRP1) is a ubiquitously expressed, multifunctional membrane receptor that combines scavenger and signaling functions regulating, among others, lipid metabolism, inflammation and fibrosis pathways, cell survival, and extracellular matrix remodeling. In acute myocardial infarction (AMI), these integrated actions of LRP1 are highly relevant because myocardial salvage and infarct healing depend on tuned control of ischemia-reperfusion injury (IRI), innate immune activation, and reparative remodeling. Despite major advances in reperfusion strategies, additional therapies are needed to blunt excessive postischemic inflammation and improve short and long-term outcomes after AMI. In preclinical models of AMI, LRP1 agonism limits IRI by promoting cardiomyocyte survival and dampening inflammatory amplification; this is accompanied by smaller infarct size, improved systolic function, reduced leukocyte-driven tissue damage, resulting in improved infarct healing and protection from adverse ventricular remodeling. Early clinical translation studies evaluated pharmacologic activation of this pathway. Recent pilot studies in patients with ST-elevation AMI using plasma-derived α1 antitrypsin, an endogenous LRP1 agonist, and synthetic peptide 16, a synthetic LRP1-agonist peptide, indicate feasibility and short-term tolerability, with preliminary signals consistent with reduced inflammatory burden and enzymatic injury, requiring further evaluation in larger randomized controlled trials. In this review, we summarize the molecular and cellular basis of LRP1 functions in the regulation of postinfarction cardiac inflammation and repair. We also discuss emerging clinical evidence supporting LRP1 as a novel therapeutic target to reduce IRI and promote infarct healing in patients with AMI. SIGNIFICANCE STATEMENT: Despite modern reperfusion strategies, maladaptive postischemic inflammation remains a major driver of adverse remodeling and heart failure. Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional receptor that integrates scavenger and signaling functions to modulate ischemia-reperfusion injury (IRI), inflammatory amplification, and postinfarction repair. This review herein synthesizes emerging preclinical and clinical evidence supporting LRP1 agonism as a novel therapeutic target to limit IRI and promote infarct healing in patients with acute myocardial infarction.

Pimavanserin was the first US Food and Drug Administration approved antipsychotic drug that does not block D2 dopamine receptors at therapeutic doses. Pimavanserin is a selective 5-HT2A receptor inverse agonist that reduces the frequency of hallucinations and delusions associated with Parkinson disease. Despite these attributes, pimavanserin prolongs the QT interval at therapeutic doses, limiting the dose to 34 mg. In addition, pimavanserin has a 57-hour half-life, and reaches steady state in approximately 12 days. ACP-204 was identified as a compound with subnanomolar affinity in radioligand binding assays, and subnanomolar inverse agonist and antagonist potency at 5-HT2A receptors in cell-based functional assays. ACP-204 had 13-fold less affinity for 5-HT2C receptors in radioligand binding, and 30- to 100-fold less potency at 5-HT2C in the functional assays, and was over 1000-fold selective against over 70 other targets. ACP-204 had 9-fold lower potency inhibiting human ether-à-go-go-related gene than pimavanserin, and lower potency at Cav1.2 L-type calcium and Nav1.5 sodium channels, all channels associated with cardiovascular function. ACP-204 was active in 3 rodent models of schizophrenia, was orally active, and potently engaged with central 5-HT2A receptors in nonhuman primates. Long-term toxicity studies demonstrated wide safety margins, and pharmacokinetic modeling predicted a 14.7 to 21.7 hours half-life in humans. It is anticipated that reducing the potential for QT prolongation will allow greater dosing flexibility with ACP-204 compared with pimavanserin; additionally, a shorter half-life may provide faster onset of action because of plasma concentrations reaching steady state sooner. ACP-204 is currently being evaluated for efficacy and safety in Alzheimer disease psychosis and Lewy body dementia psychosis. SIGNIFICANCE STATEMENT: Psychotic disorders remain a major source of burden and disability worldwide, with current treatments limited by inadequate efficacy or significant side effects. ACP-204 is a novel 5-HT2A receptor inverse agonist/antagonist being evaluated clinically for its potential to treat Alzheimer disease psychosis and Lewy body dementia psychosis. Comprehensive nonclinical evaluations shown herein demonstrate that ACP-204 has optimized pharmacodynamic properties resulting in a favorable safety/tolerability profile, a broad therapeutic index, and promising effectiveness.

Mitochondria are essential cellular organelles that were first identified in the mid-19th century. Despite more than 150 years of research and the accumulation of vast wealth of knowledge on mitochondrial structure and functions, new breakthroughs are still being made in recent years in key areas of mitochondrial biology. In the field of cancer research, major progress includes the elucidation of the role of mitochondria in cancer metabolic reprogramming, the discovery of signaling pathways in the crosstalk between mitochondria and the nucleus, the revelation of significant mitochondrial impact on tumor microenvironment and immune cells, the realization of the intriguing interplay between gut microbiota and cancer metabolism, the identification of molecular targets in mitochondria and the related pathways, and the development of mitochondria-targeted drugs such as mitocans for cancer treatment. This new progress underscores the essential role of mitochondria as multifaceted regulators of cancer metabolism, signal transduction, and cell survival, and as key pharmacological targets. This article will provide an up-to-date review of these important areas. The implications of these new research advances in cancer pharmacology and therapeutics will be explored, and interesting concepts that provide alternative theories for bioenergetics will also be discussed. SIGNIFICANCE STATEMENT: As a central hub for cellular energy production and biomolecule metabolism, mitochondria play essential roles in regulating metabolic and redox homeostasis, significantly affecting cell proliferation, survival, and sensitivity to pharmacological agents. Dysfunction of mitochondria in cancer cells alters these vital processes and affects tumor growth and therapeutic responses. Thus, a comprehensive understanding of mitochondrial alterations, the underlying regulatory mechanisms, and their impacts on pharmacological targets is pivotal for developing more effective therapeutic agents with significant clinical implications in cancer treatment.

Many attempts have been made to identify safer immunomodulatory agents that enhance the immune response and reduce the frequency and severity of infections in at-risk populations. Our previous studies have shown that Lacticaseibacillus rhamnosus CRL1505 and its postbiotics, peptidoglycan (PG1505) and cell wall (CW1505), can improve bone marrow myelopoiesis and protect mice undergoing chemotherapy against respiratory pathogens. However, the underlying mechanisms remain poorly understood. In this study, we explored both direct and indirect mechanisms using ex vivo and in vitro approaches. Oral administration of the CRL1505 strain or its cell wall significantly increased bone marrow clonogenic activity and serum G-CSF levels, as well as the percentages of myeloid progenitors (MPP and GMP) and mature cells (neutrophils and monocytes). In vitro, conditioned media from macrophages and fibroblasts stimulated with postbiotics enhanced hematopoietic activity, whereas splenocyte-conditioned media exhibited inhibitory effects on clonogenicity. Direct stimulation of bone marrow cells with the CRL1505 strain increased LSK, MPP, and GMP populations and upregulated TLR2 expression, although clonogenic activity was reduced. Interestingly, CW1505 showed a strong stimulatory effect while PG1505 elicited immune effects more closely resembling those induced by Lacticaseibacillus rhamnosus CRL1505. These findings provide new insight into the cellular and molecular mechanisms underlying the myelopoiesis-enhancing effects of novel, safe postbiotic products. They also support the therapeutic potential of these compounds for promoting immune recovery in immunocompromised patients, such as those undergoing chemotherapy. SIGNIFICANCE STATEMENT: This study demonstrates that Lacticaseibacillus rhamnosus CRL1505 and its postbiotics enhance bone marrow myelopoiesis and G-CSF production in chemotherapy-treated mice. By revealing both direct and macrophage-mediated mechanisms that regulate hematopoiesis, our findings provide new insights into how postbiotics promote immune reconstitution. The strong myelopoiesis-stimulating activity of CW1505 further supports the potential of safe, postbiotic-based immunomodulators to improve immune recovery and reduce the infection risk during chemotherapy.

Human pseudouridine synthase 7 (PUS7) catalyzes the isomerization of uridine to pseudouridine in RNA substrates. Although its catalytic region has been characterized, further studies are needed to clarify the mechanisms underlying its substrate recognition and specificity. PUS7 promotes tumor progression in glioblastoma, pancreatic adenocarcinoma, neuroblastoma, hepatocellular carcinoma, and colorectal cancer by altering RNA stability, translational fidelity, and splicing, ultimately regulating key oncogenic processes such as cell proliferation, self-renewal, metabolic reprogramming, and stress responses. Additionally, PUS7 can promote tumor progression through noncatalytic mechanisms, as observed in colorectal cancer, where it forms protein-protein complexes that activate oncogenic signaling pathways. Conversely, PUS7 exhibits tumor-suppressive functions in gastric carcinoma and papillary thyroid carcinoma by targeting mRNAs and miRNAs that regulate gene expression linked to reduced tumor aggressiveness. These findings indicate that PUS7 may represent a context-dependent therapeutic target and underscore the need for further research to clarify the molecular basis of its effects in cancer. Such knowledge may guide the development of new therapeutic strategies for PUS7-driven tumors. SIGNIFICANCE STATEMENT: Recent studies reveal that dysregulated pseudouridine synthase activity contributes to the progression of malignancies such as glioblastoma, pancreatic adenocarcinoma, neuroblastoma, colorectal cancer, and hepatocellular carcinoma. Here, we review the pseudouridine synthase's structure-function relationships and context-specific activities. The evidence discussed will help the development of selective therapeutic strategies targeting RNA modification pathways.

Restoring antigen-specific immune tolerance remains a central challenge in the treatment of autoimmune diseases, as conventional immunosuppressive therapies lack specificity and can compromise protective immunity. Tolerogenic dendritic cell (tolDC) therapies offer a promising strategy for inducing durable, antigen-specific regulatory T cell (Treg) responses, but current methods for generating tolDCs are limited by poor longevity and Treg generative capacity. This study evaluates the clinical potential of Push/Pull Immunomodulation (PPI), a novel combinatorial approach identified through high-throughput molecular screening, in human monocyte-derived dendritic cells (moDCs). The phenotype, cytokine profile, and longevity of PPI-treated moDCs were benchmarked against conventional tolDC induction agents. Functional assays assessed the capacity of PPI-tolDCs to induce antigen-specific Tregs. PPI-treated moDCs exhibited increased expression of tolerogenic markers (interleukin-10, programmed cell death receptor ligand 1, and B- and T-lymphocyte attenuator), enhanced in vitro longevity, and a unique transcriptomic signature characterized by upregulation of IDO1, IDO2, and T cell-sustaining cytokines. Notably, PPI9 induced robust, antigen-specific Treg responses, suggesting the potential for long-term tolerance induction. Although transient tumor necrosis factor-α release and moderate upregulation of CD40 and CD86 were observed, these did not impair Treg generation, indicating that PPI-tolDCs overcome key barriers associated with conventional tolDC therapies. PPI enables the generation of stable, long-lived human tolDCs with superior capacity to induce antigen-specific Tregs. Ongoing studies will further explore the translational potential of PPI-tolDCs for clinical applications in autoimmunity and transplantation. SIGNIFICANCE STATEMENT: This study validates a novel molecular combination to generate tolerogenic dendritic cells with primary human cells. These tolerogenic dendritic cells have potential use as a cell therapy for autoimmune diseases and transplantation.

Myocardial infarction (MI) is a major global health burden with limited restorative therapies. Natural compounds such as curcumin and resveratrol offer potential as adjunctive treatments. To elucidate their molecular targets and mechanisms in MI using integrated network pharmacology and summary-data-based Mendelian randomization (SMR). Potential targets of curcumin, resveratrol, and MI-related genes were retrieved from multiple databases. SMR and colocalization analyses using genome-wide association study (FinnGen R12, Million Veteran Program) and expression/protein quantitative trait loci (eQTLGen, Fenland, UK Biobank Pharma Proteomics Project, and deCODE), inferred causal links between target gene/protein expression and MI risk. Protein-protein interaction networks were analyzed for hub genes and drug-target-disease networks were constructed. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Molecular docking assessed compound-target binding. SMR analyses with subsequent validation in Million Veteran Program cohort identified 47 core targets associated with MI and potentially modulated by curcumin and/or resveratrol, exhibiting robust, genetically supported causal associations with MI risk. Further SMR, colocalization, and validation pinpointed key genes such as fibronectin 1 (FN1) and RELA (nuclear factor-κB p65 subunit) with strong MI risk associations and modulation by both compounds. Protein-protein interaction analysis identified FN1, RELA, poly(ADP-ribose) polymerase 1, Sirtuin 1, and tumor protein p53 as hub genes. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment revealed involvement in inflammation, apoptosis, oxidative stress, and key signaling pathways such as phosphatidylinositol 3-kinase/Akt signaling pathway and adenosine monophosphate-activated protein kinase. Molecular docking confirmed strong curcumin/resveratrol binding to FN1 and RELA. Curcumin and resveratrol demonstrate therapeutic potential in MI by modulating a network of targets, prominently FN1 and RELA. These actions converge on crucial protective mechanisms such as reducing inflammation and oxidative stress, providing a basis for developing novel adjunctive MI therapies. SIGNIFICANCE STATEMENT: This study identifies 47 genetically supported targets linking curcumin and resveratrol to reduced myocardial infarction risk, with fibronectin 1 and RELA emerging as key modulators. By integrating network pharmacology, summary-data-based Mendelian randomization, colocalization, and molecular docking, it reveals how these natural compounds may attenuate inflammation, oxidative stress, and cell survival pathways (eg, PI3K-Akt, AMPK), supporting their potential as adjunctive therapies to improve myocardial infarction outcomes.

Natural compounds have been a part of traditional medicine for generations, and recent studies are now recognizing their potential to influence the immune system in cancer treatment. This review focuses on how specific plant-derived chemicals can modulate immune checkpoints such as PD-1, PD-L1, and CTLA-4, which play a central role in cancer immunotherapy, mainly in preclinical and early translational studies. Compounds including curcumin, isothiocyanates, apigenin, luteolin, and berberine demonstrate mechanisms that inhibit immune evasion, are associated with enhanced cytotoxic T-cell responses, and modulate the tumor microenvironment, primarily in the in vitro and in vivo models. Several other phytochemicals such as anthocyanins, triptolide, and epigallocatechin gallate, have shown promise in preclinical models by disrupting oncogenic signaling pathways and promoting antitumor immunity. Although many of these agents face challenges such as low bioavailability, advances in drug delivery systems, and synergistic combinations with current therapies offer a compelling direction for potential cancer treatments. Understanding the molecular interactions of these natural agents can provide hypothesis generation and novel insights into potential effective and less toxic immunotherapeutic approaches. This comprehensive review further provides a thorough understanding of phytochemicals' translational and mechanistic relevance, highlights knowledge gaps, and guides future research directions that could improve integrative cancer immunotherapy techniques, noting that most of the available evidences are derived from preclinical studies. SIGNIFICANCE STATEMENT: Accumulating evidence suggests that phytochemicals modulate immune responses within the tumor microenvironment. These compounds have diverse mechanisms, ranging from cytokine modulation to effects on macrophages, T-cells, and pathways such as STAT3, NF-κB, and PD-L1. This review clarifies how phytochemicals influence immunotherapy outcomes and how they might be used more deliberately in cancer care. Unlike prior reviews, this work explicitly classifies phytochemicals according to whether they enhance antitumor immunity, suppress immune activation, or exert context-dependent dual effects relevant to immune checkpoint therapy.

Naturally occurring isothiocyanates can release hydrogen sulfide (H2S), a cardioprotective gasotransmitter involved in vascular tone regulation; however, the vascular actions of 4-hydroxybenzyl isothiocyanate (HBITC), derived from benzyl glucosinolates, have not been functionally characterized. We investigated whether HBITC exerts vasorelaxant, coronary vasodilatory, and antihypertensive effects through H2S-dependent signaling mechanisms, including Kv7 channel activation, transient receptor potential ankyrin 1 stimulation, and modulation of endogenous H2S-producing enzymes (cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase). H2S release was quantified fluorometrically in human aortic smooth muscle cells using Washington State Probe-1, membrane hyperpolarization was assessed with bis (1,3-dibutylbarbituric acid) trimethine oxonol, and vasorelaxation was examined in isolated rat aortic rings under intact, endothelium-denuded, and Nω-nitro-L-arginine methyl ester-treated conditions. Coronary flow was measured in Langendorff-perfused hearts, and the effects of blood pressure were evaluated in normotensive and spontaneously hypertensive rats. HBITC induced concentration-dependent intracellular H2S release and robust membrane hyperpolarization, comparable to the large-conductance Ca[2+]-activated K[+] channel (Kv) opener. It produced direct, endothelium-independent vasorelaxation, potentiated by intact endothelium and attenuated by nitric oxide synthase inhibition, reversibly suppressed noradrenaline-evoked vasoconstriction, restored angiotensin II-impaired coronary flow, and selectively reduced systolic blood pressure in spontaneously hypertensive rats. Collectively, these findings identify HBITC as a novel H2S-releasing vasorelaxant with antihypertensive potential and support its development as a dietary-derived scaffold for vasoprotective therapeutics. SIGNIFICANCE STATEMENT: This study identifies 4-hydroxybenzyl isothiocyanate as a previously uncharacterized dietary hydrogen sulfide donor that produces potent vasorelaxation, restores coronary flow under vasospastic conditions, and selectively lowers blood pressure in hypertensive animals. By engaging Kv7 channels, transient receptor potential ankyrin 1 signaling, and endothelial nitric oxide-hydrogen sulfide crosstalk, 4-hydroxybenzyl isothiocyanate highlights a promising natural scaffold for next-generation antihypertensive and vasoprotective therapies.

Melanoma is an aggressive and highly malignant skin cancer characterized by rapid proliferation, early metastatic dissemination, and pronounced resistance to conventional therapies, including radiotherapy. This intrinsic radioresistance is largely attributed to melanoma's high mutational burden, efficient DNA damage repair capacity, elevated antioxidant defenses, and a uniquely immunosuppressive tumor microenvironment. Consequently, improving the therapeutic efficacy of radiotherapy in melanoma remains a major clinical challenge. Recent advances in nanomedicine have introduced innovative strategies to enhance radiotherapeutic outcomes by integrating physical, chemical, and biological mechanisms of tumor sensitization. Diverse nanoplatforms, including lipid-based, polymeric, and inorganic nanoparticles, enable precise tumor targeting through passive and active mechanisms and support multifunctional therapeutic modalities. High atomic number (high-Z) nanoparticles such as gold, bismuth, and platinum amplify radiation dose deposition and reactive oxygen species generation, thereby promoting DNA damage and apoptosis. In parallel, nanoparticle-mediated photothermal and photodynamic therapies further augment radiosensitivity, whereas immune-modulatory nanocarriers enhance antitumor immune responses and synergize with immunotherapy. Importantly, beyond drug delivery, the intrinsic physicochemical properties of nanomaterials, such as catalytic activity, surface reactivity, magnetic responsiveness, and electronic features, play critical roles in modulating tumor metabolism, redox balance, and the tumor microenvironment. By highlighting preclinical and emerging clinical evidence, we outline current challenges, translational opportunities, and future directions for precision radiotherapy strategies aimed at overcoming melanoma radioresistance and improving therapeutic outcomes. SIGNIFICANCE STATEMENT: Melanoma's intrinsic radioresistance arises from rapid DNA double-strand break repair, elevated glutathione-mediated antioxidant defenses, and immune evasion. This review delineates how high-Z nanoparticles, catalytic nanozymes, and multifunctional nanocarriers enhance radiotherapy by amplifying dose deposition, generating reactive oxygen species, inhibiting DNA repair pathways, and promoting immunogenic cell death. These insights define rational design principles for nanoparticle-assisted, precision radiotherapy strategies in melanoma.

μ-Opioid receptor agonists are widely used in the treatment of pain, but produce many adverse effects. Studies suggest that co-administration of a μ-opioid receptor agonist with a δ-opioid receptor antagonist relieves pain with reduced adverse effects. We evaluated the antinociceptive effects of previously reported μ-opioid receptor agonist/δ-opioid receptor antagonist peptidomimetics in the acetic acid stretch assay and the warm water tail withdrawal (tail-flick) assay. All compounds produced anticonception in the ASSA; however, only 2 compounds, AAH8 and AMB47, produced antinociception in the tail-flick assay. the structurally similar analogs, AAH9 and AMB39, were ineffective. We hypothesized that this was due to pharmacokinetic differences. To test this hypothesis, we examined these compounds in the tail-flick assay after both intravenous and intracerebroventricular administration. Neither AAH9 nor AMB39 had any effect when given intravenously but both compounds produced antinociception after intracerebroventricular administration. AAH8 and AMB47 produced antinociceptive effects via all routes of administration. We hypothesized that crossing the blood-brain barrier was the limiting factor and tested the effects of AAH9 and AMB39 in combination with a P-glycoprotein inhibitor, Elacridar. After pretreatment with Elacridar, peripheral administration of AAH9 and AMB39 produced antinociception in the tail-flick assay. The dose-response curves for AAH8 and AMB47 were unaffected by pretreatment with Elacridar. These data suggest that even structurally similar peptidomimetics may have different pharmacokinetic properties that limit their antinociceptive effects. Understanding these pharmacokinetic properties may aid in the rational design of mixed efficacy peptidomimetic opioid ligands for the treatment of pain. SIGNIFICANCE STATEMENT: Many compounds fail out of drug development campaigns because of a lack of efficacy. One reason for this is the inability to reach the site of action. In this report, we describe 2 pairs of compounds with significantly different pharmacokinetic profiles and describe strategies for determining central nervous system penetration of opioid ligands.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, and pharmacological treatments have limited mechanistic specificity. Most nonstimulants target noradrenergic tone but show modest efficacy. l-Type calcium channels (LTCCs) modulate neuronal excitability, catecholaminergic transmission, cortical plasticity, and neuroinflammation, processes central to ADHD pathophysiology. This review evaluates the evidence for repurposing the LTCC blocker amlodipine as a novel ADHD therapeutic. We propose a mechanistic framework where amlodipine acts within attention/arousal circuits to stabilize dopaminergic and noradrenergic tone, restore D2-autoreceptor feedback, enhance plasticity, and reduce neuroinflammation. This systems-level model provides explanatory links between drug action and ADHD pathophysiology, highlighting therapeutic avenues not addressed by current treatments. Contrary to historical assumptions, recent evidence confirms that amlodipine penetrates the blood-brain barrier. Convergent preclinical findings show phenotype rescue in zebrafish and rat models of ADHD, accompanied by normalization of ADHD-relevant metabolic pathways. Complementary biobank analyses suggest reduced traits associated with ADHD among genetically at-risk individuals taking amlodipine. Given enantiomeric pharmacology, S-amlodipine, with higher LTCC affinity and fewer off-target liabilities than R-amlodipine, emerges as a preferred candidate. Together, these findings warrant a reappraisal of LTCC modulation in ADHD. By providing mechanistic explanations of how amlodipine engages ADHD-relevant circuits, this review clarifies its therapeutic potential and reshapes our understanding of the drug itself, with implications for repurposing, enantiomer-specific development, and broader clinical translation. We outline next steps, including comparative S- versus R-amlodipine studies, mechanistic dissection of LTCC subtypes in attentional networks, and controlled clinical testing to evaluate amlodipine's viability as a nonstimulant therapeutic. SIGNIFICANCE STATEMENT: Genetic, preclinical, and translational evidence implicates dysregulated l-type calcium channel signaling in attention-deficit/hyperactivity disorder, providing a mechanistic rationale for evaluating amlodipine as a therapeutic candidate. S-amlodipine is the rational development form, as it mediates the principal l-type calcium channel activity, whereas R-amlodipine may contribute to nonbeneficial brain or tolerability effects. This review defines a clear translational path focused on S-amlodipine, warranting prospective, dose-optimized clinical trials to determine efficacy on attentional and executive dysfunction with acceptable safety.