Medicines (Basel, Switzerland)最新文献

{"title":"The Role of Metabolites in Acyclovir-Induced Neurotoxicity and Nephrotoxicity.","authors":"Asma Aboelezz, Sherif Hanafy Mahmoud","doi":"10.3390/medicines13010006","DOIUrl":"10.3390/medicines13010006","url":null,"abstract":"<p><p>Acyclovir is an antiviral drug effective against infections caused by herpes simplex and varicella zoster viruses. It is given intravenously to treat serious infections such as herpes encephalitis. High acyclovir concentrations could cause toxicity, observed mainly as nephrotoxicity and, to a lesser extent, neurotoxicity. Acyclovir nephrotoxicity is primarily attributed to the crystallization of acyclovir within the renal tubules, although additional mechanisms may also contribute. However, the mechanism of acyclovir-induced neurotoxicity is unknown. Acyclovir is mainly eliminated from the body through renal excretion; however, around 15-20% of acyclovir is metabolized subsequently by alcohol and aldehyde dehydrogenase to the main metabolite 9-carboxymethoxymethylguanine (CMMG), and around 2% is metabolized by aldehyde oxidase to the minor metabolite, 8-hydroxyl acyclovir. It has been suggested that CMMG levels above 10 µmol/mL in the serum and 1 µmol/mL in the cerebrospinal fluid are highly associated with neurotoxicity. Studies have shown that there is a potential contribution of CMMG to acyclovir-induced neurotoxicity and of the acyclovir aldehyde to nephrotoxicity. In this narrative review, we approach the topic of acyclovir metabolites and their association with acyclovir toxicity. Moreover, we identify the research gap of the mechanisms by which these metabolites contribute to toxicity.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Significant Impact of Previous Major Cardiovascular Events (MACEs) and Viremia on Risk of New MACEs in People Living with HIV on Antiretroviral Therapy.","authors":"Caterina Candela, Alessia Siribelli, Tommaso Clemente, Riccardo Lolatto, Michele Bellomo, Vincenzo Stabile, Hamid Hasson, Vincenzo Spagnuolo, Antonella Castagna, Silvia Nozza, Camilla Muccini","doi":"10.3390/medicines13010004","DOIUrl":"10.3390/medicines13010004","url":null,"abstract":"<p><p><b>Background:</b> Major cardiovascular events (MACEs) in people with HIV (PWH) may be partly related to antiretroviral therapy (ART) and persistent inflammation. The aim of the study was to evaluate the association between targeted variables and MACEs. <b>Methods:</b> Retrospective, single-center study conducted on PWH receiving ART between January 2010 and April 2024, classified according to HIV-RNA levels: virological suppression (<50 copies/mL), low-level viremia (50-200 or 200-1000 copies/mL), and non-suppression (≥1000 copies/mL). Viremia was considered as a time-dependent variable and by cumulative years in each category. A Cox proportional hazards model for multivariate time-to-event analysis assessed associations between virological status and MACEs. <b>Results:</b> We included 3349 PWH followed for a median time of 14 years (interquartile range, IQR 11.2-14.2). At baseline, 2794 (83.4%) were virologically suppressed, 189 (5.6%) and 90 (2.7%) presented 50-200 and 200-1000 copies/mL, respectively, and 276 (8.2%) were non-suppressed. During the follow-up, virological suppression was documented at least once in 3295 (98.4%), low-level viremia in 1579 (47.1%) with 50-200 copies/mL and 794 (23.7%) with 200-1000 copies/mL, and HIV-RNA > 1000 copies/mL in 844 (25.2%). Overall, 300 MACEs occurred, including 53 (17.7%) repeated events, with total incident rate of 0.00976 events per person-year. The risk of MACEs was significantly associated with previous MACEs (Hazard Ratio, HR 3.385, <i>p</i>-value < 0.001) and viremia > 1000 copies/mL at baseline (HR 2.209, <i>p</i>-value 0.039). Their onset was also significantly associated with greater age at baseline and years on ART, hypertension, diabetes, lower HDL, and higher triglycerides. <b>Conclusions:</b> PWH on ART with HIV-RNA > 1000 copies/mL at baseline and a previous MACE presented higher risk of developing MACEs.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticonvulsant Therapy in Trigeminal Neuralgia: A Class-Oriented Systematic Review.","authors":"Miguel Pinto Moreira, Bruno Daniel Carneiro, Carlos Silva Faria, Daniel Humberto Pozza, Sara Fonseca","doi":"10.3390/medicines13010003","DOIUrl":"10.3390/medicines13010003","url":null,"abstract":"<p><strong>Background/objectives: </strong>Trigeminal Neuralgia (TN) is a chronic neuropathic condition characterized by sudden, severe facial pain. Anticonvulsants are the cornerstone of pharmacological management, yet comparative evidence based on pharmacological class remains scarce. This systematic review aimed to evaluate the efficacy and safety of anticonvulsants in TN, stratified by their mechanism of action.</p><p><strong>Methods: </strong>A systematic search in PubMed, Scopus and Web of Science was conducted following PRISMA 2020 guidelines. Studies employing a pharmacological approach including human patients with TN, published in English since 2000, were included. Risk of bias was assessed using the Cochrane RoB 2, the ROBINS-I and the ROBINS-E tools, according to the study design.</p><p><strong>Results: </strong>Out of 922 initial records, 12 studies met the eligibility criteria. Sodium channel inhibitors showed high efficacy but frequent adverse effects, particularly hyponatremia and central nervous system symptoms. Calcium channel modulators offered a more favorable safety profile. Combination therapies showed benefits, levetiracetam and topiramate were moderately effective and well tolerated. Although the evidence has limitations, anticonvulsants continue to be the primary treatment for TN. Sodium-channel blockers demonstrate strong efficacy, whereas alternative agents generally provide superior tolerability.</p><p><strong>Conclusions: </strong>These findings support selecting drugs according to their underlying mechanisms of action. Equally important is tailoring therapy to pain phenotype and patient characteristics, balancing mechanism with tolerability and efficacy.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidant Delivery Revisited: The Promise of Nanostructured Lipid Carriers.","authors":"Leif Behar, Holly Siddique","doi":"10.3390/medicines13010002","DOIUrl":"10.3390/medicines13010002","url":null,"abstract":"<p><p>Natural products have an invaluable therapeutic effect on human health. Natural antioxidants, including beta-carotene, turmeric, and polyphenols, are recognised for their health benefits but face significant barriers related to insufficient solubility, instability, volatility, and diminished bioavailability, which limit their therapeutic efficacy in drug delivery systems. Therefore, encapsulation of natural products in a carrier addresses the above concern. Drug delivery systems, such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), are promising carriers for effective release, consisting of solid and liquid lipids, which enhance efficiency, stability, and controlled release, thereby minimising bioavailability limitations. This review consolidates current studies on the formulation methodologies, mechanisms of action, and therapeutic applications of NLCs, emphasizing their use in the treatment of conditions such as cancer, neurological disorders, and cardiovascular diseases. The results demonstrate that NLCs substantially enhance the bioavailability and therapeutic efficacy of antioxidants, thereby improving their targeted administration and clinical effects. Nonetheless, difficulties in clinical translation remain, including drug loading capacity, regulatory authorisation, and the need for pervasive research on cytotoxicity. This article highlights important areas for future inquiry, specifically the optimisation of NLC formulations, the enhancement of targeting accuracy, and the resolution of safety issues to enhance their clinical application.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment of Symptomatic Male Hypogonadism with New Oral Testosterone Therapies: A Comparative Review of Jatenzo, Tlando, and Kyzatrex.","authors":"Samantha H Rosen, Kian Asanad","doi":"10.3390/medicines13010001","DOIUrl":"10.3390/medicines13010001","url":null,"abstract":"<p><p>Symptomatic male hypogonadism, defined by low serum testosterone with associated clinical symptoms, is increasingly treated with testosterone replacement therapy. Traditional oral formulations were limited by hepatotoxicity and poor bioavailability, leading to reliance on injectable and transdermal routes. Recent advances in oral testosterone undecanoate formulations have introduced safer and more effective options. This review compares Jatenzo, Tlando, and Kyzatrex, highlighting their pharmacology, efficacy, safety, and clinical utility. Clinical trial data demonstrate restoration of eugonadal testosterone levels in most patients (80-88%), with shared risks including hypertension, polycythemia, and lipid changes. Differences in dosing regimens, titration requirements, and insurance coverage influence choice of therapy and patient adherence. Kyzatrex offers flexible titration and self-pay access, Tlando provides a fixed-dose regimen, and Jatenzo combines titratability with established clinical data. Collectively, these agents expand the therapeutic landscape of hypogonadism, offering effective, non-invasive alternatives that support individualized treatment strategies.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12821475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preliminary Evaluation of an Injectable Therapeutic for Cisplatin Ototoxicity Using Neuronal SH-SY5Y Cells.","authors":"Michelle Hong, Katherine Kedeshian, Larry Hoffman, Ashley Kita","doi":"10.3390/medicines12040030","DOIUrl":"10.3390/medicines12040030","url":null,"abstract":"<p><strong>Background/objectives: </strong>Though ototoxic, cisplatin is a mainstay of chemotherapy for a variety of cancers. One suggested mechanism of cisplatin ototoxicity involves damage to the spiral ganglion afferent neurons in the inner ear. There is a need for a high-throughput model to screen medications for efficacy against cisplatin and to develop a local therapeutic to mitigate cisplatin's debilitating side effects. Microparticles encapsulating a therapeutic medication are an injectable and tunable method of sustained drug delivery, and thus a promising treatment.</p><p><strong>Methods: </strong>SH-SY5y human neuroblastoma cells were used as a cell line model for the spiral ganglion neurons. The cells were dosed with cisplatin and four potential therapeutics (melatonin, metformin, cyclosporine, and N-acetylcysteine), with cell viability measured by CCK-8 assay. The most promising therapeutic, N-acetylcysteine (NAC), was then encapsulated into multiple poly(lactic-co-glycolic acid) (PLGA) microparticle subtypes of varied lactide-glycolide (L:G) ratios and NAC amounts. The elution profile of each microparticle subtype was determined over two months.</p><p><strong>Results: </strong>Of the therapeutics screened, only cells dosed with 1 or 10 mM NAC prior to cisplatin injury demonstrated an improvement in cell viability (73.8%, <i>p</i> < 1 × 10^-8) when compared to cells dosed with cisplatin alone. The 75:25 L:G microparticles demonstrated an increase in the amount of NAC released compared to the 50:50 L:G microparticles.</p><p><strong>Conclusions: </strong>NAC is a potential therapeutic agent for cisplatin toxicity when tested in a neuronal cell line model. NAC was encapsulated into PLGA microparticles and eluted detectable concentrations of NAC for 6 days, which is a first step towards otoprotection for the weeks long duration of chemotherapy treatment. This work describes a method of screening potential therapeutics and a strategy to develop local drug eluting treatments to protect against cisplatin ototoxicity.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"12 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12735174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Active Components in <i>Connarus ruber</i> Extract Exhibiting Anti-Glycation Effects.","authors":"Ryoji Taniguchi, Ryusuke Nakatsuka, Yuka Sasaki, Mariko Takenokuchi, Takashi Maoka, Tomio Iseki, Hirohito Kubo, Tadashige Nozaki","doi":"10.3390/medicines12040029","DOIUrl":"10.3390/medicines12040029","url":null,"abstract":"<p><strong>Background: </strong>Glycation, a non-enzymatic reaction between sugars and biomolecules, leads to the formation of advanced glycation end-products (AGEs), which are implicated in the progression of chronic diseases. <i>Connarus ruber</i> (Poepp.) Planch (<i>C. ruber</i>), a traditional medicinal plant used for diabetes, has shown anti-glycation activity. This study aimed to identify the active components in <i>C. ruber</i> extract and elucidate their anti-glycation mechanisms.</p><p><strong>Methods: </strong>Using NMR and LC-MS analyses, we identified epicatechin and procyanidin A2 as major polyphenolic constituents. Collagen glycation assays were performed to evaluate the inhibitory effects of these compounds on fructose- and glyceraldehyde (GA)-induced glycation. Additionally, their cytoprotective effects were assessed using GA-induced cytotoxicity assays in dental pulp stem cells (DPSCs).</p><p><strong>Results: </strong>Both epicatechin and procyanidin A2 inhibited fructose- and GA-induced glycation in a dose-dependent manner, showing greater efficacy than aminoguanidine. Furthermore, these compounds significantly alleviated GA-induced cytotoxicity in DPSCs.</p><p><strong>Conclusions: </strong>These findings suggest that epicatechin and procyanidin A2 are candidate contributors to the anti-glycation and cytoprotective effects of <i>C. ruber</i>. The results support the potential of <i>C. ruber</i> extract as a source of therapeutic agents for glycation-related diseases and for enhancing stem cell viability.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"12 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12734466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AΙ-Driven Drug Repurposing: Applications and Challenges.","authors":"Paraskevi Keramida, Nikolaos K Syrigos, Marousa Kouvela, Garyfallia Poulakou, Andriani Charpidou, Oraianthi Fiste","doi":"10.3390/medicines12040028","DOIUrl":"10.3390/medicines12040028","url":null,"abstract":"<p><p>Drug repurposing is the process of discovering new therapeutic indications for already existing drugs. By using already approved molecules with known safety profiles, this approach reduces the time, costs, and failure rates associated with traditional drug development, accelerating the availability of new treatments to patients. Artificial Intelligence (AI) plays a crucial role in drug repurposing by exploiting various computational techniques to analyze and process big datasets of biological and medical information, predict similarities between biomolecules, and identify disease mechanisms. The purpose of this review is to explore the role of AI tools in drug repurposing and underline their applications across various medical domains, mainly in oncology, neurodegenerative disorders, and rare diseases. However, several challenges remain to be addressed. These include the need for a deeper understanding of molecular mechanisms, ethical concerns, regulatory requirements, and issues related to data quality and interpretability. Overall, AI-driven drug repurposing is an innovative and promising field that can transform medical research and drug development, covering unmet medical needs efficiently and cost-effectively.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"12 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12641654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145590134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabis Use and Analgesic Prescribing in UK Primary Care: A Retrospective Cohort Study of Patients with Osteoarthritis.","authors":"Simon Erridge, Joht Singh Chandan, Krishna M Gokhale, Christian Billinghurst, Mikael H Sodergren","doi":"10.3390/medicines12040027","DOIUrl":"10.3390/medicines12040027","url":null,"abstract":"<p><strong>Objectives: </strong>This study aims to assess differences in analgesia prescribing in UK primary care between individuals with osteoarthritis who have a recorded exposure to cannabis use and those who do not.</p><p><strong>Methods: </strong>This population-based retrospective cohort study included opioid-naïve patients with osteoarthritis (aged 25-85 years) who were active in Clinical Practice Research Datalink Aurum between 1 January 1995 and 15 December 2023. Patients with osteoarthritis who had current or historic cannabis use recorded were matched to two unexposed individuals by age, sex, smoking status, and health authority. Patients were followed up to assess prescriptions of analgesia. Cox regression was performed adjusted for age, sex, and ethnicity.</p><p><strong>Results: </strong>662 exposed patients were matched to 1319 unexposed patients. Cannabis-exposed individuals were more likely to be prescribed opioids (adjusted hazard ratio (HR): 2.06; 95% confidence interval (CI): 1.74-2.43; <i>p</i> < 0.001), gabapentinoids (HR: 3.31; 95% CI: 2.34-4.67; <i>p</i> < 0.001), non-steroidal anti-inflammatory drugs (HR: 1.99; 95% CI: 1.72-2.31; <i>p</i> < 0.001), tricyclic antidepressants (HR: 2.64; 95% CI: 2.03-3.44; <i>p</i> < 0.001), other antidepressants (HR: 7.22; 95% CI: 5.24-9.94; <i>p</i> < 0.001), and paracetamol (HR: 3.30; 95% CI: 2.43-4.48; <i>p</i> < 0.001).</p><p><strong>Conclusions: </strong>This study suggests there is an association between coded exposure to cannabis in UK primary care records and increased prescribing of analgesia. Given the relative scarcity of recorded cannabis use relative to its prevalence in the general population, these findings must be interpreted cautiously. The increased hazard of using analgesia and mortality within the cannabis-exposed cohort may be confounded by socioeconomic status and a higher likelihood of coding cannabis use in those experiencing adverse effects after consumption or cannabis misuse disorder.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"12 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12641637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145590089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC5 Inhibition as a Therapeutic Strategy for Titin Deficiency-Induced Cardiac Remodeling: Insights from Human iPSC Models.","authors":"Arif Ul Hasan, Sachiko Sato, Mami Obara, Yukiko Kondo, Eiichi Taira","doi":"10.3390/medicines12040026","DOIUrl":"10.3390/medicines12040026","url":null,"abstract":"<p><strong>Background/objectives: </strong>Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (<i>TTN</i>) truncating variants (<i>TTN</i>tv). While <i>TTN</i>tvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking <i>TTN</i> deficiency to cardiac dysfunction and maladaptive fibrotic remodeling remain incompletely understood. This study aimed to identify key epigenetic regulators of <i>TTN</i>-mediated gene expression and explore their potential as therapeutic targets, utilizing human patient data and in vitro models.</p><p><strong>Methods: </strong>We analyzed RNA sequencing (RNA-seq) data from left ventricles of non-failing donors and cardiomyopathy patients (DCM, HCM, PPCM) (GSE141910). To model <i>TTN</i> deficiency, we silenced <i>TTN</i> in human iPSC-derived cardiomyocytes (iPSC-CMs) and evaluated changes in cardiac function genes (<i>MYH6</i>, <i>NPPA</i>) and fibrosis-associated genes (<i>COL1A1</i>, <i>COL3A1</i>, <i>COL14A1</i>). We further tested the effects of TMP-195, a class IIa histone deacetylase (HDAC) inhibitor, and individual knockdowns of HDAC4/5/7/9.</p><p><strong>Results: </strong>In both human patient data and the <i>TTN</i> knockdown iPSC-CM model, <i>TTN</i> deficiency suppressed <i>MYH6</i> and <i>NPPA</i> while upregulating fibrosis-associated genes. Treatment with TMP-195 restored NPPA and MYH6 expression and suppressed collagen genes, without altering <i>TTN</i> expression. Among the HDACs tested, HDAC5 knockdown was most consistently associated with improved cardiac markers and reduced fibrotic gene expression. Co-silencing <i>TTN</i> and <i>HDAC5</i> replicated these beneficial effects. Furthermore, the administration of TMP-195 enhanced the modulation of <i>NPPA</i> and <i>COL1A1</i>, though its impact on <i>COL3A1</i> and <i>COL14A1</i> was not similarly enhanced.</p><p><strong>Conclusions: </strong>Our findings identify HDAC5 as a key epigenetic regulator of maladaptive gene expression in <i>TTN</i> deficiency. Although the precise mechanisms remain to be clarified, the ability of pharmacological HDAC5 inhibition with TMP-195 to reverse <i>TTN</i>-deficiency-induced gene dysregulation highlights its promising translational potential for <i>TTN</i>-related cardiomyopathies.</p>","PeriodicalId":74162,"journal":{"name":"Medicines (Basel, Switzerland)","volume":"12 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12641632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145590106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}