Transient receptor potential melastatin 3 (TRPM3) is a calcium-permeable ion channel implicated in chronic pain and developmental and epileptic encephalopathies. The voltage sensor-like domain (VSLD) is a major site of pharmacological modulation, but the molecular determinants of ligand recognition and efficacy remain incompletely understood. Here we combine cryo-electron microscopy, molecular dynamics simulations, mutagenesis, and medicinal chemistry to investigate the interactions of TRPM3 with the inhibitors isosakuranetin, maprotiline, and diclofenac. We show that structurally diverse ligands occupy a common VSLD cavity but engage distinct interaction networks. Functional and computational analyses identify ligand-specific residue dependencies and support a halogen bond between diclofenac and D947 that contributes to inhibitor potency. Furthermore, esterification or amidation of the diclofenac carboxylate converts inhibition into potentiation, and mutagenesis and molecular dynamics simulations support partially overlapping VSLD configurations associated with these opposing effects. Together, these findings establish the TRPM3 VSLD as an adaptable allosteric pocket in which ligand-specific interactions shape recognition, potency, and efficacy.

Retinitis Pigmentosa (RP) is a group of inherited retinal degenerations for which most subtypes lack effective drug treatments. This challenge is particularly critical for autosomal dominant (ad) RP, which is often unsuitable for gene replacement therapy. To address this challenge, we screened an FDA-approved compound library using a zebrafish adRP model expressing a human RHODOPSIN transgene with the Q344X mutation. The screen evaluated drug effects on larval visual behavior by assessing the visual-motor response (VMR). Four compounds significantly improved VMR in Q344X zebrafish: amitriptyline, difluprednate, maprotiline, and prednisolone. Further characterization revealed that these hits act through distinct mechanisms, including reducing rod death, promoting rod neogenesis, and enhancing the function of extraocular photoreceptors. Together, these findings demonstrate the potential to repurpose these drugs for adRP caused by the RHO Q344X mutation, providing preclinical candidates and revealing potential targets for future drug development.

Glaucoma is a leading cause of irreversible blindness, primarily due to elevated intraocular pressure (IOP) that damages the retina and optic nerve. Most topical glaucoma treatments focus solely on IOP-lowering without direct neuroprotection, as drug delivery to the posterior eye is challenging. Here, we developed NeuProIO, a dual-action solid drug nanoparticle (NP) eye drop for simultaneous IOP reduction and neuroprotection. Using flash nanoprecipitation in a multi-inlet vortex mixer, we fabricated the first NeuProIO solid drug NPs incorporating the repurposed neuroprotective agent maprotiline (MAP) and the IOP-lowering agent betaxolol (BX), forming MAP/BX NPs for synergistic glaucoma treatment. The NeuProIO improved stability and ocular biocompatibility versus conventional eye drops and markedly enhanced corneal transport. Single topical dosing sustained an effective IOP control (15% IOP reduction or higher) for 72 h. Beyond its IOP-lowering effect, BX significantly enhanced the posterior segment delivery of MAP in MAP/BX NPs, resulting in retinal and optic nerve MAP levels that were approximately 5-fold and 2-fold higher, respectively, than those observed with MAP alone. In silicone oil-induced ocular hypertension glaucoma mouse model, the MAP/BX combination exhibited significantly improved neuroprotection effects than MAP monotherapy, including >21% greater ganglion cell complex thickness, >7-fold axon preservation, and >4-fold retinal ganglion cell survival. A comprehensive biosafety evaluation confirmed the safety of NeuProIO, with assessments of corneal thickness, RGC viability, and major organ histology revealing no adverse local or systemic effects. Taken together, NeuProIO has the potential to redefine glaucoma treatment, offering a more effective and long-lasting solution to preserving vision and improving patient outcomes.

Digital twin models can accelerate therapeutic development by enabling low-risk testing of candidate interventions. In preterm labor (PTL), a major pregnancy complication where clinical trials face unique ethical and financial barriers, digital twins are especially valuable for evaluating new therapies targeting immune dysfunctions driving PTL. Yet, current models lack single-cell resolution, limiting detection of cell-type-specific mechanisms, off-target effects, and the design of personalized interventions. We present Simulated Immunome Modeling of Clinical Outcomes (SIMCO), a single-cell-level digital twin framework that models immunomodulatory treatment effects on the timing of labor using immunome-wide, single-cell simulations. SIMCO's digital twins are trained and validated on a newly generated mass cytometry atlas of the pregnant immunome exposed to nine candidate drugs preselected for PTL prevention. Applying SIMCO to an independent cohort of pregnant individuals, we simulate treatment effects on gestational length, screening for candidate drugs that delay labor timing and providing system-level mechanistic insight for each drug candidate. Tetrahydrofolate, maprotiline, and the combination of aspirin and lansoprazole emerged as top candidates for PTL prevention, delaying labor onset primarily through enhanced mTOR signaling in innate immune cells and attenuated JAK/STAT signaling in naïve CD4[+] T cells. The codebase is available at https://github.com/ofondeur/SIMCO/.

Current therapeutic approaches for colorectal cancer (CRC) face challenges such as recurrence and drug resistance. Ferroptosis, a novel form of cell death, is a promising therapeutic approach for CRC. SPOP plays an important biological role as a substrate-binding protein of the E3 ubiquitin ligase complex CRL3, but its therapeutic effects in CRC patients and its ability to modulate ferroptosis remain largely unknown. This study demonstrated that SPOP functions as a tumor suppressor in CRC and that SPOP inhibits the proliferation and metastasis of CRC cells and increases their sensitivity to ferroptosis. Transcriptome analysis suggested that Wnt signaling may be a potential target for the function of SPOP. Further data revealed that SPOP knockdown increased β-catenin protein levels, and the clinical data indicated that SPOP expression had the opposite effect on β-catenin protein levels. Molecular biology experiments suggest that SPOP promotes polyubiquitination and degradation of the K508 site of β-catenin. Interestingly, O-GlcNAcylation of SPOP reduces its protein stability and affects SPOP binding to β-catenin, and SPOP also promotes CRC ferroptosis by inhibiting the β-catenin/SLC7A11 axis. Combined treatment with the SPOP-targeted drug maprotiline and a ferroptosis inducer has synergistic antitumor efficacy in CRC cells and xenografts. Our study reveals the multifaceted function of SPOP in CRC, and the activation of SPOP may be a feasible strategy to increase the sensitivity of CRC to ferroptosis inducers.

Antidepressants induce physiological alterations; however, the degree to which these occur in treatment with various antidepressants is unclear. We aimed to compare and rank antidepressants based on physiological side-effects by synthesising data from randomised controlled trials (RCTs).

T-cell lymphoma (TCL) is a prevalent malignancy characterized by the aberrant proliferation of T cells. The molecular mechanism underlying TCL remains poorly understood, and effective therapeutic strategies are still limited. Maprotiline, a highly selective norepinephrine reuptake blocker, is primarily used in the treatment of various types of depression. Intriguingly, its potential therapeutic utility and underlying mechanisms in TCL have not been previously explored. In this study, we demonstrated for the first time that maprotiline significantly inhibits proliferation and migration while promoting apoptosis in TCL cells. Furthermore, in vivo experiments using TCL xenograft mouse models revealed that maprotiline treatment effectively suppresses tumor progression while maintaining a favorable safety profile with minimal toxicity. Mechanistically, our findings reveal that maprotiline exerts its anti-tumor effect by regulating the AKT/mTOR signaling pathway in TCL. Notably, we discovered that maprotiline substantially enhances the sensitivity of TCL cells to histone deacetylase inhibitor, thereby unveiling a promising combination therapeutic strategy for TCL treatment. These findings not only expand our understanding of maprotiline's pharmacological potential beyond its conventional antidepressant use, but also provide a novel therapeutic avenue for addressing the clinical challenges in TCL management.

Caffeine consumption is regarded as a widespread phenomenon, and its usage has continued to increase. In addition, the growing usage of antidepressants worldwide and increase in mental health disorders were shown in recent statistical analyses conducted by the World Health Organisation. The coadministration of caffeine and antidepressants remains a concern due to potential interactions that can alter a patient's response to therapy. This review investigates the pharmacokinetic and pharmacodynamic interactions between caffeine and the five main classes of antidepressants: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and other antidepressants not categorised by class, which we have categorised as 'miscellaneous'. The interaction between fluvoxamine and caffeine resulted in increased concentrations of caffeine in the body and lowered the renal clearance of fluvoxamine. Other SSRIs such as fluoxetine and escitalopram had augmented antidepressant effects by decreasing their renal clearance and prolonging their effects in the body when coadministered with caffeine. Caffeine may also increase the concentration of paroxetine, potentially affecting its pharmacodynamic effects. TCAs such as clomipramine, imipramine, desipramine, and sertraline, were found to reduce the metabolism of caffeine. However, studies suggest caffeine had no significant effect on the concentration of these medications in blood or brain tissue. The inhibition of caffeine at high doses when used with MAOIs such as tranylcypromine and phenelzine was found to lead to a higher likelihood of experiencing hypertension. Coadministration of caffeine with venlafaxine (SNRIs) suggests minimal interactions between the two substances and the pharmacodynamic effects of venlafaxine were unlikely to be impacted by caffeine consumption. Miscellaneous antidepressants (reboxetine, mianserin, agomelatine, maprotiline, and mirtazapine) displayed varying pharmacodynamic interactions with caffeine, resulting in increased antidepressant effects where vortioxetine, maprotiline, and mirtazapine failed to demonstrate any interactions. In conclusion, caffeine demonstrated varying effects on the pharmacokinetic and pharmacodynamic properties of each class of antidepressants, with several classes of antidepressants demonstrating a similar effect on caffeine.

Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side effects of current ICIs, such as programmed death protein-1, programmed cell death-ligand 1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibodies, there is an urgent need to find new drugs with ICP inhibitory effects. In this study, a network-based computational framework called multi-network algorithm-driven drug repositioning targeting ICP (Mnet-DRI) is developed to accurately repurpose novel ICIs from ≈3000 Food and Drug Administration-approved or investigational drugs. By applying Mnet-DRI to PD-L1, maprotiline (MAP), an antidepressant drug is repurposed, as a potential PD-L1 modifier for colorectal and lung cancers. Experimental validation revealed that MAP reduced PD-L1 expression by targeting E3 ubiquitin ligase speckle-type zinc finger structural protein (SPOP), and the combination of MAP and anti-CTLA4 in vivo significantly enhanced the antitumor effect, providing a new alternative for the clinical treatment of colorectal and lung cancer.

Because there is little published experience with maprotiline during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.