The development of foam cells is crucial in the advancement of atherosclerosis (AS). Tanshinone IIA (Tan IIA), the primary lipophilic component of Salvia miltiorrhiza, has various pharmacological effects. Despite this, the precise role of Tan IIA in AS has not been fully elucidated. In this research, we employed ApoE-/- mice to establish an AS model. Oil Red O and HE staining indicated that Tan IIA obviously reduced plaque areas in both the aorta and aortic arch. Additionally, serum analysis revealed that Tan IIA notably decreased lipid and inflammatory factor levels in AS mice. In vitro studies showed that Tan IIA primarily prevented foam cell formation by enhancing cholesterol efflux rather than increasing lipid uptake. Mechanistic investigations reveal that Tan IIA suppresses the Hedgehog (Hh) signaling pathway by downregulating the expression of transient receptor potential melastatin 2 (TRPM2) and subsequently inhibiting Ca²⁺ influx. This cascade ultimately attenuates foam cell formation and impedes the progression of AS. Overall, this research provides a solid theoretical foundation for the potential application of Tan IIA in the treatment of AS.

Cilia beating of ependymal cells regulates adult neural stem cell quiescence via mechanical forces mediated by PKD1/2-TRPM3.

Transient receptor potential melastatin 3 ion channel expressed in sensory neurons mediates osteoarthritis pain in mice.

TRPM8-dependent protective effects of L-menthol attenuates lipid overload-induced calcium dysregulation and mitochondrial dysfunction in mouse ventricular myocytes.

The TRPM family: key players and mechanisms in energy metabolism.

In the 2025 novel drug mini-review, one can take a full measure of the ingenuity that underlies current drug design and development, despite the year's smaller harvest (46 novel drugs) compared to 2024 (53) and 2023 (70). 54% of the novel drugs are first-in-class (FIC). The emphasis on proteins/antibodies is maintained (~25% novel drugs in 2025), an industry trend that does not seem to abate. Fewer than half of the novel medicines address major or common disorders. Among the FIC drugs, it is worth mentioning the Nav1.8 channel inhibitor suzetrigine, the first non-opioid approved to palliate acute pain; the first positive allosteric modulator of transient receptor potential melastatin 8 (TRPM8), acoltremon, that increases basal tear production in dry eye disease, a globally common disorder; lerodalcibep, a 'third generation' adnectin inhibitor of the protease Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) to treat elevated LDL-c; and zoliflodacin and gepotidacin, both innovatively targeting bacterial topoisomerases to treat uncomplicated urinary tract infections. Most of the approved medicines target unmet medical need areas and/or orphan indications (the latter alone accounting for 41% of the 2025 novel drugs) by applying imaginative approaches. These approaches include: the combination of two FIC drugs, the RAF/MEK clamp avutometinib paired with the FAK/Pyk2 inhibitor defactinib, to block more efficiently the RAS-RAF-MEK-ERK/FAK oncogenic pathway in low-grade serous ovarian cancer; fitusiran, the first RNAi therapy for haemophilia, targeting for the first time the production of the natural anticoagulant anti-thrombin in the liver; and brensocatib, which attenuates the activation of downstream neutrophil proteases by inhibiting the protease DPP1, thereby preventing lung tissue destruction in bronchiectasis. The landscape of novel drugs approved in 2025 reveals that pharmaceutical innovation continues to advance through FIC mechanisms, sophisticated therapeutic approaches, and a strong focus on unmet medical need.

To evaluate the safety and efficacy of the transient receptor potential melastatin 8 agonist acoltremon on signs and symptoms of dry eye disease (DED). Two identical randomized, multicenter, double-masked, vehicle-controlled phase 3 studies. Adults aged 30 years or older with a DED diagnosis, at least 1 eye with both total corneal fluorescein staining (tCFS) score of 2 or more and 15 or less (no region scoring less than 3) and anesthetized Schirmer test score of 2 or more and less than 10 mm/5 min, and both ocular discomfort (visual analog scale) and Symptom Assessment iN Dry Eye (SANDE) scores of 50 or more. Patients (COMET-2, N = 465; COMET-3, N = 466) were randomized 1:1 to acoltremon 0.003% (ACO) or vehicle twice daily for 90 days (ClinicalTrials.gov identifiers: COMET-2, NCT05285644; COMET-3, NCT05360966). The primary end point was the proportion of patients achieving a 10-mm or greater increase in unanesthetized Schirmer test (UST) score on day 14. The key secondary end point was change from baseline (CFB) in global SANDE score on day 28. Additional secondary end points included CFB in UST on days 1 and 90. Exploratory end points included CFB in tCFS and total conjunctival staining. The primary end point was met in both studies, with more patients receiving ACO achieving a 10-mm or greater increase in UST on day 14 (ACO vs. vehicle: COMET-2, 42.6% vs. 8.2%; COMET-3, 53.2% vs. 14.4%; P < 0.0001 for both). Reduction in global SANDE score by day 28 (key secondary end point) favored ACO in both studies, and was statistically significant in COMET-2. Increased tear production favored ACO versus vehicle as early as day 1 through day 90 in both studies (P < 0.0001). Greater reductions with ACO were observed in tCFS on days 28 and 90 and in total conjunctival staining at all time points. Mild instillation-site burning/stinging was the only ocular adverse event reported with an incidence of more than 2.5%. In COMET-2 and COMET-3, ACO compared with vehicle led to consistent, clinically meaningful tear production and reductions in DED signs and symptoms. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Hypoxic-ischemic brain injury (HIBI) is a major cause of perinatal brain damage, contributing to significant neonatal mortality and disability, yet its therapeutics remain limited. Transient receptor potential melastatin 7 (TRPM7), a channel-kinase with kinase activity involved in neuronal death and neuroinflammation, has been implicated in ischemic and hypoxic brain damage. Although the ion channel function of TRPM7 has been widely explored, the specific contribution of its kinase activity to HIBI pathophysiology remains poorly understood, mainly due to the lack of potent TRPM7 kinase inhibitors. TG100-115 (TG) is the first identified potent TRPM7 kinase inhibitor. Using a neonatal mouse model of HIBI, we examined the in vivo neuroprotective effects of TG across different treatment paradigms, including pre-treatment and post-treatment at various time points. TG significantly reduced infarct volume when administered before HIBI or up to 3 h post-HIBI, improved brain morphology, and enhanced both short- and long-term functional recovery. Mechanistically, TG treatment normalized TRPM7 protein levels, modulated caspase-3-associated apoptotic pathway, and preserved neuronal integrity. Additionally, TG attenuated the NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, indicated by reduced expression of NLRP3 and its adaptor protein ASC, as well as IL-18 levels, suggesting a role in modulating neuroinflammation. These findings demonstrate that TG protects against HIBI by modulating TRPM7 expression and apoptotic signaling, and suppressing NLRP3 inflammasome-associated neuroinflammation. This study highlights the pharmacological inhibition of TRPM7 kinase as a promising therapeutic strategy for HIBI. TG100-115, a TRPM7 kinase inhibitor, provides neuroprotection and attenuates NLRP3 inflammasome-mediated neuroinflammation in a neonatal mouse model of hypoxic-ischemic brain injury.

Microglia, the resident immune cells of the central nervous system, play a pivotal role in neuroinflammation and is a key contributor to the onset and progression of various neurological and neurodegenerative diseases. The Transient Receptor Potential Melastatin 2 (TRPM2), a non-selective calcium channel, has emerged as a sensor linking oxidative stress responses and calcium influx. It is expressed in many tissues and cells, including neurons, astrocytes, and microglia. TRPM2 represents one of the molecular mediators regulating microglial activity and function, cytokine production, and microglia-neuron communication. Growing evidence suggests that TRPM2 contributes to the pathological mechanisms underlying diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, epilepsy, and neuropathic pain. However, most of the studies mainly explored the TRPM2 involvement in cell death, which has been reviewed by some other authors. In this review, we compile and discuss findings from in vivo and in vitro studies evaluating the role of TRPM2, with a specific focus on its influence over microglial function and neuroinflammatory responses, a field that has been poorly explored. We gathered information from studies reporting, in stroke models, that both pharmacological inhibition and genetic deletion of TRPM2 reduced infarct volume, improved behavioral outcomes, and diminished glial reactivity. In models of neurodegeneration, TRPM2 modulation shows promising effects on neuronal survival and microglial phenotype. In neuropathic pain models, TRPM2 was found to mediate microglial activation and the release of pro-inflammatory mediators, contributing to pain hypersensitivity. However, findings in epilepsy models reveal a more complex picture, with TRPM2 deficiency producing either neuroprotective or deleterious outcomes, highlighting the need for further studies. Although most studies to date support a pathogenic role for TRPM2 in microglia-mediated neuroinflammation, some limitations were highlighted, as the non-selective pharmacological inhibitors available, the inclusion of only males in the majority of studies, and the use of a global TRPM2 knockout. Only two studies employed conditional genetic models to promote specific TRPM2 deletion from microglia, with promising findings. Overall, current evidence indicates TRPM2 as a promising modulator of microglia, with broad implications for the treatment of neurological disorders characterized by chronic inflammation.

Bemisia tabaci is a globally damaging pest for which insecticide reliance and resistance demand eco-rational, mechanism-informed alternatives. This study aimed to build a multi-tier pipeline of (TRP) channel docking, Y-tube olfactometry, RNA interference (RNAi) functional validation, and field trapping to identify and mechanistically support plant volatile attractants for improved monitoring/management. Docking of 51 volatile organic compounds against six modelled TRP receptors (Transient Receptor Potential Cation Channel Subfamily A Member 1 (TRPA1), TRPV-Inactive, TRPL, Transient Receptor Potential Melastatin (TRPM), TRPML, TRPP-PKD1) yielded binding energies from -3.2 to -7.6 kcal mol-1, with TRPM/TRPA1 showing the most stable interactions; shortlisted ligands showed ΔG -5.9 to -7.6 kcal mol-1 and Ki 2.7-47.3 μM. In Y-tube assays (five concentrations: 10000-1 ppm, n = 5), attraction was ligand-dependent (F = 1852.03, P < 0.0001); top ligands reached Amax ~0.61-0.66, including thymol (olfactory preference index up to 0.66 ± 0.04), cis-3-hexen-1-ol (up to 0.62 ± 0.05), β-caryophyllene (up to 0.61 ± 0.04), cuminaldehyde (up to 0.61 ± 0.03), and phenylacetaldehyde (up to 0.64 ± 0.04). RNAi feeding caused strong, time-dose knockdown: at 250-500 ppm, TRPA1 and TRPM transcripts dropped to ~0.18-0.13 fold (24-48 h), while combined dsTRPA1 + dsTRPM reached minima ~0.05-0.04 fold; behavioural attraction fell from ~0.58-0.65 (control/double stranded Green Fluorescent Protein (dsGFP)) to ~0.15-0.19 (dsTRPM) and ~0.02-0.19 (dsTRPA1), with dual knockdown reaching -0.02 to 0.13 (1 ppm). Field trials (three chrysanthemum fields, randomized complete block design, 10 ligands + control) showed 2.1-3.2× higher catches than control (F10,66 = 41.07, P < 0.0001); thymol peaked at 42.1 ± 2.8 adults trap-1 (AI = 3.17, CV = 6.6%) and retained 128.5% efficacy by day 6. The convergence of docking affinity, lab attraction, RNAi-dependent behavioural suppression, and consistent field performance supports TRPA1/TRPM as key contributors to volatile-guided orientation and delivers validated attractants (notably thymol, β-caryophyllene, cuminaldehyde) for stronger, more reliable whitefly monitoring and semiochemical-based integrated pest management. © 2026 Society of Chemical Industry.

Exposure to drug of abuse produces strong drug reward-associated environmental contextual memories, which contribute to driving compulsive drug-seeking behaviors or even relapse upon cue exposure. The anterior cingulate cortex (ACC), a pivotal brain region involved in regulating decision-making and motivation, has recently been found to be activated in methamphetamine (METH) users when exposed to drug cues; however, its underlying mechanisms remain elusive. Here, we utilized a METH-induced conditioned place preference (CPP) model in mice to investigate the role of the ACC and to explore the potential molecules in the retrieval of METH-associated memories. We found that the glutamatergic neurons in the ACC were significantly activated during the METH CPP test. Further, chemogenetic suppression of ACC glutamatergic neurons effectively blocked METH-induced CPP. By RNA sequencing analysis, we found that transient receptor potential melastatin 3 (TRPM3), a non-selective cation channel, was upregulated in ACC glutamatergic neurons following METH CPP, with a concomitant increase in the phosphorylation levels of its downstream molecules-extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB). Most importantly, either local pharmacological inhibition of ACC TRPM3 activity with isosakuranetin (ISO) or selective knockdown of TRPM3 levels in ACC glutamatergic neurons significantly attenuated the METH-induced CPP. Collectively, our findings demonstrate that TRPM3 in ACC glutamatergic neurons plays a critical role in modulating METH reward-associated memory, highlighting TRPM3 as a potential therapeutic target for METH-induced abnormal neuro-behaviors.

Arterial hypertension (HT) is a major risk factor in the pathogenesis of cardiovascular diseases and has a high prevalence. The pathogenesis of primary HT, which accounts for the majority of HT cases, has not been fully elucidated; therefore, effective treatment targets remain an important area of research. Transient receptor potential (TRP) channels represent a distinct class of cation channels that play a pivotal role in signal transduction by altering membrane potential or intracellular Ca2+ concentration. Based on sequence similarity, TRP channels are classified into six subfamilies: TRP canonical (TRPC), TRP melastatin (TRPM), TRP vanilloid (TRPV), TRP mucolipin (TRPML), TRP ankyrin (TRPA), and TRP polycystin (TRPP). These channels exhibit broad expression across diverse tissues and cell types and play critical roles in numerous pathophysiological processes through the regulation of ion concentrations (Ca2+, Mg2+, Na+, and K+) and the modulation of intracellular signal transduction pathways. Research involving human subjects, as well as experimental models, highlights the essential role of TRP channels in maintaining vascular homeostasis and regulating blood pressure. TRP channels, particularly TRPCs, have gained increasing attention for their role in resistant HT, a condition in which blood pressure remains uncontrolled despite the use of multiple antihypertensive drugs. Additionally, these channels have been identified as central mediators of inflammation and oxidative stress, processes that are pivotal in the pathogenesis of cardiovascular disorders, including HT. This review summarizes current evidence on TRPC, TRPV, and TRPM channels in HT, highlighting emerging translational findings and potential therapeutic implications.

Cardiovascular diseases remain the leading global cause of death and disability, prompting the need for precise mapping of molecular drivers that couple ionic flux to signaling. Because of its regulatory role in ionic balance and signaling, transient receptor potential melastatin 7 (TRPM7) channel-kinase has emerged as a key molecular determinant of cardiovascular physiology and pathophysiology. Following an overview of Ca2+ signaling in cardiovascular biology, we summarize current knowledge of TRPM7 from its structure to its function, including channel architecture, gating properties, and kinase regulation by metabolic and redox signals with a diverse substrate repertoire. Integration of evidence across cardiovascular systems biology shows that TRPM7 acts in a context-dependent manner. In the vasculature, TRPM7 shapes endothelial function, smooth muscle phenotype and remodeling, and participates in neurogenic control of blood pressure through carotid body glomus cells. In the heart, TRPM7 regulates pacemaking and conduction through transcription control of ion channel genes, contributes to atrial fibrogenesis via Ca2+-dependent fibroblast activation, and worsens ischemia-reperfusion injury through ionic overload and inflammasome signaling. In metabolic heart disease, TRPM7 kinase activity links mitochondrial oxidative stress to diastolic dysfunction, suggesting relevance to heart failure with preserved ejection fraction (HFpEF). Finally, we appraise pharmacological tools that target TRPM7, including natural and synthetic channel and kinase modulators, and outline translational considerations for organ- and disease-specific modulation. Overall, TRPM7 is a central integrator of ionic homeostasis and kinase signaling in cardiovascular biology and represents a promising, yet nuanced, therapeutic target that requires context-aware strategies.

Temperature-sensitive transient receptor potential melastatin subfamily 4 (TRPM4) ion channels convert intracellular calcium increases into membrane depolarization, thereby linking these two powerful cellular signaling pathways in diverse physiological processes. TRPM4 mutations cause severe human hereditary cardiovascular and skin diseases; mysteriously, while these mutations are gain-of-function in nature, they affect the heart and the skin in a mutually exclusive manner. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP2) lipid is a required cofactor for TRPM4 activity by tightly regulating its calcium sensitivity. We detected two PIP2 binding sites and located the high-affinity site adjacent to the S4-S5 linker. We demonstrated that skin disease-associated TRPM4 mutations relieve the tight control of PIP2, resulting in elevated channel activity but only at the body surface temperature. In contrast, heart diseases are associated with mutations known to boost the number of channels, an effect we found to be annihilated by channel desensitization outside the body core. Indeed, dendritic cells from transgenic mice carrying a skin disease mutant exhibited elevated migration at 25-to-30°C range compared to those from normal mice, but no difference was observed at 37°C. These findings shed light on a molecular mechanism for dynamic regulation of cellular signaling in physiology and diseases.

The pathological mechanism underlying retinal apoptosis in X-linked retinoschisis (XLRS), a disease caused by retinoschisin 1 (RS1) deficiency, remains incompletely understood. This study aimed to investigate the role of transient receptor potential melastatin 1 (TRPM1) in retinal tissues and cells. Retinal function and structure were assessed by electroretinography (ERG) and optical coherence tomography (OCT). Protein expression was evaluated by immunofluorescence staining and western blotting (WB). Retinal morphology was examined by hematoxylin and eosin (H&E) staining. Apoptotic retinal cells were detected by TUNEL staining. Key proteins were screened using proteomics data obtained by mass spectrometry. Intracellular calcium levels were measured using Rhod-2 AM. TRPM1 expression in Rs1-KO mice was 1.3-fold higher than that in wild-type mice (p < 0.05), whereas TRPM1-overexpressing ARPE19 cells exhibited approximately twofold higher expression than the empty vector control group. Mechanistically, TRPM1-mediated calcium influx promoted calcium/calmodulin-dependent protein kinase II (CAMKII) phosphorylation. Concomitantly, the accumulation of the autophagy-related proteins P62 and LC3B, increased BAX expression, and decreased BCL2 expression were observed in both Rs1-KO retinal tissues and TRPM1-overexpressing ARPE19 cells. These findings collectively suggest that TRPM1 may contribute to cell's apoptosis. Our study provides new insight into the mechanism of retinal apoptosis in XLRS.

The transient receptor potential melastatin 3 (TRPM3) channel is a key mediator of peripheral pain signaling, and pathogenic mutations in TRPM3 are linked to neurodevelopmental delay and epilepsy. Despite the therapeutic promise of TRPM3 modulators, the molecular mechanisms by which ligands modulate channel gating remain poorly understood. Here, we combine cryo-electron microscopy (cryo-EM) with functional analyses to characterize a promiscuous ligand-binding pocket formed by transmembrane helices S1-S4. This pocket accommodates several chemically diverse plant-derived and synthetic agonists and antagonists. We show stereoselectivity of TRPM3 for the (R)-enantiomer of the flavonoid antagonist isosakuranetin and the (R)-enantiomer of the synthetic agonist CIM0216. Mutations within this pocket-including variants identified in patients -alter ligand affinity and, in some cases, invert the functional outcome of ligand binding. These findings reveal the stereoselectivity and functional plasticity of the TRPM3 ligand-binding pocket, highlighting how subtle changes in the molecular interactions can produce divergent effects on channel gating, with important ramifications for TRPM3-targeted drug development and therapy.

Electrical signals serve as important modulators in bone regeneration, yet recreating this self-sustaining bioelectrical microenvironment at the peri-implant interface remains challenging. In this study, we engineered pyroelectric nanostructure coatings on titanium (Ti) implants to enhance implant osteointegration through temperature fluctuation-driven electrical stimulation. The pyroelectric titanium (pyroTi) implants leverage the combined effects of the pyroelectric effect and cold stimulation to amplify calcium ion (Ca2+) influx by activating cold-sensitive transient receptor potential melastatin 8 (TRPM8) ion channel, therefore driving osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). As a demonstration, pyroTi usedas a dental implant in the rabbit maxilla showed enhanced osteointegration under routine cold-water intake. This study establishes a proof of concept for pyroelectric biomaterials that harness physiological temperature variations to potentiate bone-implant integration.

ABSTRACT Objective Cerebral edema is a major contributor to mortality in diverse pathologies; regretfully, no effective therapies can reduce the associated damage. In cerebral ischemia, ionic edema formation is mediated by the sulfonylurea receptor 1 (SUR1)/transient receptor potential melastatin 4 (TRPM4) complex expressed in brain endothelial cells. Given that Resveratrol reduces the damage induced in human brain endothelial cells (HBEC-5i) subjected to oxygen-glucose deprivation (OGD)/reoxiygenation (R) by down-regulating SUR1 expression, we aimed to determine whether Resveratrol modulates SUR1-TRPM4 activity in this model. Methods HBEC-5i cells were exposed to OGD for 2 h followed by 24 h of R. Intracellular Na+ accumulation, measured with the Na-sensitive fluorescence probe coronaNa Green, was used as an indicator of SUR1-TRPM4 activity. Immunofluorescence assays were performed to evaluate SUR1 and TRPM4 expression. Resveratrol (5 μM) was administered during OGD/R. Diazoxide was used to identify responding cells. Results Resveratrol reduced the increase in intracellular Na+ induced by OGD/R and linked to SUR1/TRPM4 activation. While the basal SUR1 and TRPM4 expression levels were low, OGD/R induced their overexpression. Nonetheless, their intracellular distribution indicated incomplete co-localization. A subset of cells showed Na+ elevation after OGD/R, suggesting that although many cells expressed SUR1 and TRPM4, most did not form functional complexes. Diazoxide increased Na+ influx exclusively in ‘responding’ cells, confirming functional SUR1-TRPM4 activity in this subpopulation. Conclusion SUR1-TRPM4 becomes functionally expressed in a subset of HBEC-5i during OGD/R and pretreatment with Resveratrol attenuated this response. Early modulation of SUR1-TRPM4 by Resveratrol may represent a potential strategy to limit ionic edema.

Transient receptor potential melastatin 1 (TRPM1) is a membrane protein essential for vision in dim light, and mutations in TRPM1 cause complete congenital stationary night blindness. Although TRPM1 shares sequence similarity to other TRPM ion channels such as TRPM3, whether it independently functions as an ion channel remains controversial. This controversy is largely caused by TRPM1’s challenging biochemical behaviors that prevent detailed molecular characterization. In this work, we isolate TRPM1 and determine its structures using cryogenic electron microscopy (cryo-EM). The structures reveal a canonical tetrameric fold in the intracellular domain, consistent with other TRPM family members that are ion channels. Surprisingly, in the transmembrane domain, despite the presence of the conserved voltage sensor-like domain (VSLD) and pore domain (PD) in a domain-swapped fashion, the VSLD and PD are arranged with an opposite handedness compared to other related channels. This inverted transmembrane domain allows the formation of a large pore-like structure that supports the role of TRPM1 as an ion channel. This non-canonical architecture of TRPM1 may also confer unique permeation and pharmacological properties.

Abstract Background Genetic testing has significantly advanced the diagnosis of arrhythmias by establishing associations to specific genes. While numerous well-established genes have been implicated in Long QT Syndrome, the dynamic nature of genetic mutations suggests that additional genes may yet be discovered in association with cardiac genetic disorders. A case report from China proposed a potential association between TRPM4 gene with congenital Long QT Syndrome. However, the association of TRPM4 gene with Long QT Syndrome remains largely unexplored. Purpose The aim of this report is to identify the association of transient receptor potential melastatin 4 (TRPM4) gene with the incidence of Long QT Syndrome. Methods We reported a case of a 64-year-old male patient who presented to the emergency department following a near-syncope episode. He reported two prior near-syncope incidents and had initially received a diagnosis of transient ischemic attack. Notably, his father had experienced a similar episode, although no other family members reported related symptoms. Additionally, the patient is managing uncontrolled hypertension and was subsequently referred to a cardiologist to exclude any cardiac-related causes for his symptoms. A blood sample was collected for whole exome sequencing (WES), and bioinformatics tools were employed to analyse the data for inherited diseases. Results An electrocardiogram (ECG) revealed sinus rhythm with a prolonged QT interval measuring 546 ms, while echocardiography results were within normal limits. A 24-hour Holter monitor assessment indicated a corrected QT interval (QTc) of 546 ms, with no documented episodes of near syncope. Genetic testing was conducted, which identified a heterozygous variant of uncertain significance (VUS) in exon 19 of the TRPM4 gene (chr19:49703929C&amp;gt;A, c.2840C&amp;gt;A, p.Ala947Asp). Notably, approximately 97% of known TRPM4 missense variants are classified as VUS, posing significant challenges in diagnosis and clinical management. The patient was started on propranolol to reduce the QT interval. Following treatment, he has not experienced further near-syncope episodes. Subsequent monitoring a month later recorded a reduction in QTc to 515 ms. The patient remains on propranolol but declined the option of an implantable cardiac defibrillator due to financial constraints. Conclusions The TRPM4 gene variant identified in this case has not been established as a genetic cause of Long QT Syndrome. This case may contribute valuable insights into the genetic pathogenesis of Long QT Syndrome associated with TRPM4 gene variants, warranting further investigation.