Aging is a major risk factor for chronic diseases, driving an urgent need for effective geroprotectors. Repurposing psychotropic agents offers an efficient strategy to accelerate anti-aging therapeutics development. In this study, we investigated the effects of pimozide (a diphenylbutylpiperidine-class antipsychotic) on aging in Caenorhabditis elegans and elucidated the underlying mechanisms. The results demonstrated that 0.1 μM pimozide significantly extends nematode lifespan, increasing mean, median, and maximum lifespans by 44.3%, 50.0%, and 39.8%, respectively. Furthermore, pimozide improves healthspan, as evidenced by reduced age-related lipofuscin accumulation, preserved locomotor function, and decreased paralysis incidence. Moreover, pimozide-treated nematodes showed enhanced resistance to heat, ultraviolet and oxidative stress, concomitant with reduced endogenous reactive oxygen species levels. Transcriptomic profiling and biochemical validation reveal that pimozide markedly upregulates collagen gene expression and increases hydroxyproline content, indicating enhanced collagen synthesis. Mechanistically, pimozide promotes the nuclear localization of SKN-1, and its beneficial effects on lifespan extension and collagen synthesis are SKN-1-dependent, as these effects are abolished in skn-1 mutants. Collectively, our findings demonstrate that pimozide promotes longevity and healthspan by activating skn-1, which is accompanied by enhanced collagen synthesis, providing a preclinical proof of concept for its potential repurposing as a geroprotector.

Multiple myeloma (MM) remains an incurable blood cancer. Obesity is a known risk factor, but how adipocytes promote MM progression is not fully understood. Here, we uncover a metabolic crosstalk between adipocytes and MM cells that promotes MM cell survival under glucose deprivation. We show that glucose restriction activates AMPK, disrupting HSP90-IRF4 binding and rendering IRF4 susceptible to TRIM21-mediated proteasomal degradation. Paradoxically, the same stress stimulates adipocytes to produce β-hydroxybutyrate (β-OHB). MM cells utilize β-OHB through OXCT1-mediated ketolysis, fueling NAT10-dependent acetylation of IRF4 at K87, which restores IRF4-HSP90 binding and sustains tumor cell survival. Genetic ablation of the rate-limiting ketogenic enzyme Hmgcs2 in adipocytes abrogates this protective effect. Importantly, combining an AMPK activator (metformin) with an OXCT1 inhibitor (pimozide) or a NAT10 inhibitor (remodelin) shows synergistic anti-tumor activity in vivo. Our findings position adipocyte-derived β-OHB as a critical metabolic adaptor and highlight a potential combination therapy for MM.

Poor aqueous solubility and complex supersaturation behaviour of small-molecule drugs require rapid, material-sparing analytical tools that capture incipient aggregation and phase separation events under non-equilibrium conditions. This work evaluated a miniaturised optical platform that combined second harmonic scattering (SHS) with linear light scattering (LLS) driven by an ultrafast 1030 nm laser to monitor supersaturated solutions of 12 poorly water-soluble drugs prepared by DMSO solvent shift in 384-well plates. LLS and SHS signals were recorded after 1 h and 24 h and compared with apparent solubilities from a parallel solvent-shift HPLC assay. LLS, which reports on particle size/number, detected precipitation onsets typically close to or below HPLC values and could resolve particle formation down to ∼ 0.1 µM for pimozide, substantially exceeding the sensitivity of standard nephelometric methods. SHS, which is sensitive to interfacial asymmetry and nonlinear susceptibility, often showed onsets and complex peak-drop-rise patterns that deviated from LLS, particularly for lopinavir, loratadine, and ritonavir, indicating structurally distinct, largely centrosymmetric drug-rich assemblies above the solubility limit. Orthogonal characterization by scanning electron microscopy, Capflex (capillary flow with a hydrophobic fluorescent tracer), and confocal fluorescence microscopy provided independent evidence for droplet-like or amorphous drug-rich domains that preceded bulk precipitation. Together, the results showed that combined SHS-LLS enabled highly sensitive detection of precipitation, while revealing multistep, non-classical aggregation pathways in pharmaceutical supersaturated systems.

Pimozide overdose is uncommon, with limited published cases worldwide. Its long elimination half-life predisposes to delayed and prolonged toxicity, including extrapyramidal symptoms (EPS) that may mimic neuroleptic malignant syndrome (NMS). Herein, we report a case of a 33-year-old female with dysthymic disorder, recurrent depression, and obsessive-compulsive disorder who presented with rigidity, mutism, psychomotor retardation, and reduced responsiveness for 4 days. She had intentionally ingested around 20-30 pimozide tablets 4 days prior. Initial suspicion of catatonia was revised after the patient disclosed overdose. She developed fever (100°F), worsening rigidity, tremors, and ankle clonus. Creatine phosphokinase (CPK) was mildly elevated at 523 U/L, which argued against NMS. Fever resolved with antibiotics, and EPS improved with supportive care and levodopa-carbidopa. However, the patient developed aspiration pneumonia and succumbed. Thus, pimozide overdose can cause severe EPS mimicking NMS. Differentiation relies on CPK levels and fever response. Supportive care and prolonged observation are critical for favorable outcomes.

Chronic filarial infections remain a global health burden, with limited adulticidal therapies highlighting the need for new drugs. We explored repurposing human GPCR antagonists, including clemizole, pimozide, proroxan, and suloctidil, along with 45 rationally designed analogs for activity against Brugia pahangi and two Onchocerca species. Of those, 27 showed in vitro adulticidal activity. In vivo, clemizole and analog C-8 significantly reduced worm burden by 60.5% and 50.8%, respectively, while S-17 and PMZ-6 modestly reduced worm burden (36% and 25%, respectively); however, all three significantly reduced worm fecundity. C-8 also downregulated GPCR expression in surviving adult females after in vivo treatment. Radioligand binding assays revealed selective human GPCR affinities, with clemizole and suloctidil analogs having increased parasite selectivity. Caenorhabditis elegans reverse genetics screen identified gar-3 and ser-7 as putative nematode targets of clemizole and its analogs. Clemizole, C-8, and S-17 represent promising leads for further optimization as antifilarial drugs.

Accurate determination of ligand structures in protein-ligand complexes is essential for elucidating molecular recognition mechanisms and advancing structure-based drug discovery. Cryogenic electron microscopy (cryo-EM) has emerged as a powerful technique for determining macromolecular structures; however, reliable identification of small-molecule ligands from cryo-EM maps remains challenging, particularly in the absence of accurate initial ligand models. Here, we present MLAC (MicroED-assisted Ligand structure Analysis in Complexes), an integrative framework that combines microcrystal electron diffraction (MicroED) with cryo-EM single-particle analysis (SPA). In MLAC, high-resolution ligand structures determined by MicroED from submicrometer-sized crystals are used as initial models for fitting into cryo-EM maps of protein-ligand complexes. As a proof of concept, previously reported hERG-ligand complexes were reanalyzed. MicroED structures of representative hERG ligands-astemizole, pimozide, and E-4031-were determined at resolutions of 0.66-0.92 Å and then used for model fitting and refinement. Several quantitative metrics, including Q-score, atom inclusion, model-to-map correlation coefficients, clash analysis, and Mogul analysis, together with visual inspection, indicated that MicroED-derived ligand structures can facilitate ligand modeling for astemizole and, to a lesser extent, pimozide, whereas no clear advantage was observed for E-4031. Notably, MicroED frequently revealed structural polymorphs that provided alternative ligand conformations and helped resolve modeling ambiguities, including the chair-boat conformational variability of the piperidine ring and alternative ligand placements in the hERG-astemizole complex. Collectively, these findings support MLAC as a proof-of-concept framework that provides experimentally determined starting models to complement computational ligand-generation approaches.

Health, social, and ethical considerations highlight the need for new male contraceptives. Pimozide is an FDA approved drug known to block T-type calcium channels and which shares structural similarities with mibefradil, a proven antagonist of the CatSper channel. In this study, we examined the effect of pimozide on CatSper, a key target for non-hormonal male contraception. Molecular docking and molecular dynamics simulations were carried out to assess how pimozide binds within the channel pore, and binding energies were estimated using MM-GBSA. To determine its impact on sperm function, we evaluated hyperactivation, the acrosome reaction, and CatSper activity. Our computational analyses indicate that pimozide functions as a pore blocker of the CatSper channel. Experimental findings further support this, showing that pimozide inhibits CatSper activity, and impairs hyperactivation and the acrosome reaction in human spermatozoa. Overall, these results identify pimozide as a novel CatSper antagonist and propose a binding mode, offering a basis for the rational design of reversible, non-hormonal male contraceptives that target the CatSper channel.

Dopamine D2 receptor antagonists/partial agonists (D2RAs), including the US Food and Drug Administration-approved Tourette syndrome (TS) agents haloperidol, pimozide, and aripiprazole and other antipsychotics with dopamine D2 receptor-modulating properties, are prescribed for TS. This retrospective real-world study compared adverse events (AEs) and health care resource utilization (HCRU) between pediatric patients with TS newly treated versus not treated with D2RAs.

Dermatological delusional disorders, such as delusional infestation (DI), are a unique type of psychosis in which the patient experiences specific delusions, such as parasites or inorganic materials that come out of their skin. Originally, this type of "encapsulated psychosis" was thought to be unresponsive to antipsychotic agents. However, over the past half a century, several medications with antipsychotic properties have been found to be effective in the treatment of these conditions in the USA, especially pimozide and risperidone. Despite effective treatments, several challenges may arise for clinicians in successfully treating patients with these conditions. These challenges include selecting an efficacious medication and skillfully practicing diplomacy and empathy while guiding patients toward effective management. Navigating interactions with patients with DI and their frequent denial of a psychiatric component to their condition often poses additional challenges to patient-provider rapport and proper and timely management. In the USA, many patients with DI are opposed to trying the conventional approach of psychiatric care and immediate trial of antipsychotic medications. This manuscript represents a single-center psychodermatology perspective on managing dermatologic delusional disorders. This article synthesizes clinical experience from a US clinic and situates that experience within the available evidence. High-quality comparative data are limited. Therefore, this paper highlights pragmatic engagement strategies, pharmacotherapy principles, essential safety monitoring, and research priorities. Experience-based recommendations are clearly labeled as such.

A recent study delves into intricate relationship between microRNAs (miRNAs), specifically focusing on their role in cancer development. miRNAs are highlighted for their capacity to modify genetic profile and modulate epigenetic architecture, establishing regulatory circuit between epigenetic modulation and miRNAs. Notably, antipsychotic drugs, particularly pimozide, is reported to influence miRNA expression, impacting essential processes in cancer development such as cell proliferation and apoptosis. Anti-cancer properties of pimozide have sparked interest in its potential role in cancer treatment, although precise mechanism of its antitumor function remains elusive. The study focuses on a newly discovered miRNA, miR-2909, encoded by the apoptosis antagonizing transcription factor (AATF) gene, which has been implicated in oncogenesis. This research aims to unravel the interplay between pimozide and miR-2909, investigating their influence on epigenetic modulations and their functional relevance to cellular proliferation and apoptosis in cancer cells. Utilizing bioinformatic tools for structural prediction, pharmacokinetic property assessment, and molecular docking interactions, the study reveals a strong binding affinity between pimozide and miR-2909.Validation through various experimental methods, including qRT-PCR, western blotting, immunofluorescence, transient transfection, CHIP assay, and flow cytometry confirms the interplay between pimozide and miR-2909. The results demonstrate a pivotal role in the regulation of genes responsible for cellular proliferation and apoptosis. Additionally, the study uncovers that pimozide's pharmaco-epigenomic response is mediated through miR-2909, promoting DNA methylation and leading to decreased cellular proliferation, increased apoptosis, ROS generation, and altered cell-cycle dynamics. In conclusion, the findings identify pimozide as a potential chemotherapeutic agent acting through the regulation of the oncomiR-2909. Insight Box This study uncovers a novel pharmaco-epigenomic mechanism by which the antipsychotic drug pimozide exerts anti-cancer effects in breast and lung cancer cells. We demonstrate that pimozide downregulates oncogenic miR-2909, leading to the upregulation of DNMT3B, which mediates epigenetic silencing of key proliferation genes and promotes apoptosis. This integrative approach-combining molecular biology, gene expression profiling, and epigenetic analysis-provides new biological insight into the repurposing of psychiatric drugs for cancer therapy. Our findings highlight the therapeutic potential of targeting microRNA-epigenetic interactions and suggest a broader applicability of integrating pharmacology with systems biology to uncover unconventional roles of known drugs in cancer treatment.

Chronic lymphocytic leukemia (CLL) progression and therapeutic resistance are driven in large part by protective signals from the tumor microenvironment (TME), which includes T-cell-derived cytokines such as interleukin-4 (IL-4) that promote survival via signal transducer and activator of transcription (STAT) signaling and upregulation of antiapoptotic proteins such as the B-cell lymphoma 2 (BCL-2) family member myeloid cell leukemia 1 (MCL-1). Although the BCL-2 inhibitor venetoclax has demonstrated significant clinical efficacy, microenvironment-induced resistance, particularly by MCL-1 upregulation, remains a major limitation. Here, we identify the US Food and Drug Administration-approved antipsychotic drug pimozide as a dual-function agent that induces lysosome membrane permeabilization, leading to apoptosis in CLL cells through increased reactive oxygen species production. In addition, pimozide inhibited STAT5 phosphorylation, reduced IL-4-induced MCL-1 expression, and prevented IL-4/CD40L-mediated inhibition of apoptosis. Importantly, pimozide remains effective in inducing apoptosis in CLL cells from patients who have relapsed after therapy. Pimozide also synergizes with venetoclax to induce apoptosis in CLL cells even after IL-4/CD40L signaling. This suggests that dual targeting of lysosomal function and STAT signaling represents a promising therapeutic approach to improve venetoclax efficacy and overcome TME-mediated drug resistance in CLL.