Search Results (315)

Peptidylarginine deiminases (PADs) are a family of five isozymes (PAD1–4, PAD6) in humans, with PAD2, 3 and 4 associated with the central nervous system. PAD-mediated post-translational citrullination/deimination of target proteins contributes to pathobiological processes, including in the central nervous system (CNS), where the potential of PAD inhibitor treatment has been reported. This study aimed to identify PAD-dependent pro-regenerative responses in neuronal and astrocytic cells, respectively, using human cellular in vitro models to assess the therapeutic effects of pan-PAD, PAD2- and PAD4 isozyme-specific inhibitors in an oxygen–glucose deprivation/reperfusion model of ischaemia (OGD/R) at different time windows (30 min, 1 h and 4 h) in conjunction with scratch injury and LPS stimulation. Key findings suggest that pan-PAD inhibitor Cl-amidine promotes CNS regeneration through enhancing wound-healing of both neuronal and astrocytic cells, indicating roles for several PAD isozymes in acute CNS injury. Astrocyte cells showed the most prominent PAD4 detection, with significantly lower levels of PAD1, PAD2, PAD3 and PAD6, while differentiated SH-SY5Y neuronal cells showed the highest detection of PAD3, followed by PAD2 and PAD1, as well as strong PAD6 positivity, but negligible PAD4 detection. Histone H3 citrullination was significantly reduced in response to Cl-amidine treatment in both cell types, indicating changes in histone H3-dependent events in CNS injury. Cl-amidine treatment modulated key neuronal (beta-3 tubulin) and astrocytic (GFAP) markers and also reduced inflammatory cytokine IL-6 levels in astrocytes following 4 h OGD/R in conjunction with LPS stimulation. This study indicates roles for several PAD isozymes, with differing prominence in neurons and astrocytes, and emphasises the potential for pharmacological PAD inhibitor treatment in CNS injury. Full article

Approximately 30% of all human cancers are driven by mutations in RAS genes, KRAS, HRAS, and NRAS, resulting in the constitutive activation of RAS proteins and stimulation of MAPK/AKT signaling. Non-mutant, i.e., wild-type (WT) RAS can also become activated through mechanisms such as gene amplification or excessive stimulation by mutated or overexpressed receptor tyrosine kinases (e.g., EGFR), thereby promoting cancer progression. Mutant or activated RAS contributes to multiple hallmarks of cancer, including unchecked cellular proliferation, reprogrammed cellular metabolism, immunosuppression, and metastasis. Hence, RAS is of immense clinical importance, with hundreds of laboratories studying various aspects of RAS biology or developing RAS inhibitors. There is perhaps no greater unmet medical need in oncology than the need for a broadly efficacious but safe inhibitor of mutant and activated RAS. Mutant-specific KRAS G12C inhibitors have shown promising therapeutic efficacy, leading to FDA approval of sotorasib and adagrasib, although their use is limited to patients with the relatively rare G12C KRAS mutation. Mutant-specific KRAS inhibitors are also susceptible to adaptive resistance, in part, due to secondary RAS mutations, and compensatory signaling from WT RAS isozymes. A pan-RAS inhibitor capable of blocking all RAS isozymes, regardless of the underlying mutation, offers the potential for broader efficacy and capacity to avert resistance. While just a few years ago, pan-RAS inhibitors were predicted to be severely toxic or even fatal, the apparent safety profile of RMC-6236 (daraxonrasib), a pan-RAS inhibitor currently in clinical trials, suggests otherwise. Indeed, pan-RAS inhibitors are now considered by many in the RAS field to be the most promising class in development. In this review, we summarize the evolution and current status of pan-RAS and pan-KRAS inhibitors in preclinical and clinical development and highlight emerging human-relevant tumor models that are advancing preclinical evaluation. Full article

Interpretation of pharmacometabolomics results, aiming particularly at biomarker (sets) discovery for drug exposure, remains a major challenge. The metabotyping of drug exposure depends on resolution of specific metabolomics techniques and comprises individual metabolic phenotypes (“metabotypes”), disease-, drug- and microbiome-specific patterns, as well as conditional metabolic states (e. g. fasting). In this clinical trial with 16 healthy participants, an exploratory objective was to evaluate the untargeted urinary metabolomics of voriconazole, administered in four single doses, using proton nuclear magnetic resonance (¹H-NMR) spectroscopy. Voriconazole is a second-generation triazole and a potent inhibitor of drug-metabolizing enzymes such as cytochrome P450 (CYP) isozymes CYP3A4 and CYP2C19. Therefore, identification of metabolites reflecting acute CYP3A4 inhibition was of particular interest. On two treatment days without and with voriconazole (with background microdosed midazolam and omeprazole administration for CYP3A4 and CYP2C19 phenotyping, respectively), spot urine was collected after overnight fasting (predose) and 4 h later (postdose fasting). In the postdose versus predose fingerprints, most changes at the annotated metabolite level were attributable to fasting metabolomics or potential confounders. ¹H-NMR spectroscopy identified neither a short-term voriconazole-specific signature nor patterns or metabolites potentially reflecting acute CYP3A4 inhibition. Our study emphasizes crucial significance of strict standardization of fasting time and minimization of confounder influences by clinical trial design as well as selection of adequate baselines and high-resolution analytical techniques in pharmacometabolomics research, especially for biomarker discovery. Full article

Background: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), increase colorectal cancer (CRC) risk. Methods: Mouse IBD and CRC models with a combination of pharmacological, knockout and knock-in approaches was employed to analyze the involvement of TOP2s and NOS2 in CRC tumorigenesis. Key pathologies, such as inflammatory and neoplastic scores, were examined by immunohistochemical assays. Results: In colon tissues from acute, chronic colitis and CRC mouse models and from CD patients, the biomarkers γH2AX and 53BP1_pS25/S29 of DNA breaks (mainly representing DSBs) accumulated, alongside increases in topoisomerase II (TOP2) and nitric oxide synthase 2 (NOS2). Genetic ablation of NOS2 (Nos2^-/-) or TOP2β (Top2β^f/f) as well as pharmacological inhibition with ICRF-193 (a TOP2 inhibitor) or PTIO (a NO scavenger) reduced DSB formation and disease severity. Consistently, Nos2^-/-, or ICRF-treated, mice exhibited decreased tumor burden. DSBs and tumor accumulation were pronounced in the distal colon, mirroring human CRC distribution. While ICRF-193 suppressed tumor growth, Top2β^f/f deficiency (with a compensatory TOP2α upregulation) enhanced tumor development, indicating potential roles for TOP2 isozymes in tumor formation and progression. Conclusion: Collectively, these findings identify the cooperative action of TOP2 and NOS2 in driving DSBs, highlighting a potential therapeutic target in inflammation-associated CRC. Full article

The Swine hepatitis E virus (SHEV) ORF3 protein is pivotal in pathogenesis, yet its regulation of host metabolic homeostasis via endogenous RNA networks remains unclear. This study aimed to elucidate how the SHEV ORF3-mediated circRNA-miRNA network modulates riboflavin metabolism and triggers the aberrant activation of the ko05212 pathway, while also evaluating their physical interactions using AlphaFold 3 structural simulations. To achieve this, high-throughput RNA sequencing, KEGG pathway analysis, and AlphaFold 3 structural simulations were employed to elucidate the circRNA-miRNA-mRNA regulatory network and potential physical interactions. Transcriptomics revealed a “dual activation” of Riboflavin metabolism and Pancreatic cancer pathways. Specifically, we identified an “ENPP Isozyme Switch,” where upregulated hsa_circ_0077855 sponges miR-181a-2-3p, relieving repression of the metabolic enzyme ENPP3 and proto-oncogene KRAS. Furthermore, AlphaFold 3 simulations yielded an extremely low interface predicted Template Modeling score (ipTM = 0.08), refuting direct physical binding, and ORF3 was found to suppress the m6A eraser FTO, suggesting host epigenetic instability. Consequently, SHEV ORF3 induces metabolic remodeling through a dual “epigenetic-post-transcriptional” mechanism: disrupting m6A homeostasis via FTO suppression and constructing a pathogenic ceRNA network via the ENPP3/miR-181a/KRAS axis. These findings highlight the critical role of non-coding RNAs in driving the virus-induced “pre-pathological state”. Full article

Background: Obesity is a multifactorial chronic disease resulting from sustained energy imbalance and modulated by environmental and demographic factors, and it is associated with numerous comorbidities. DNA methylation is an epigenetic modification associated with obesity. Modulation of DNA methylation is a viable target for obesity control strategies. The flavanol (-)-epicatechin (EC) exerts beneficial effects in overweight individuals, suggesting that EC may influence gene regulation through signaling pathways and epigenetic mechanisms. We evaluated whether EC modulates obesity-associated DNA methylation changes using complementary in silico, in vitro, and in vivo approaches. Methods. In silico analyses were performed to explore potential EC interactions with the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. DNMT activity was measured in nuclear extracts of 4T1 cells in the presence of EC. Finally, in a C57BL/6 mouse model of diet- induced obesity, we assessed global DNA methylation and the expression of the DNA methyltransferases, as well as metabolism-related genes; peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc-1α), pyruvate dehydrogenase kinase isozyme 4 (Pdk4), and nuclear factor erythroid 2–related factor 2 (Nrf2) and relative mitochondrial DNA content (mtDNA/nDNA ratio) in visceral adipose tissue (VAT) and skeletal muscle. Results. EC showed stable in silico interactions within catalytic/cofactor-binding regions of DNMTs and inhibited DNMT activity in vitro in a concentration-dependent manner. In vivo, the obesogenic diet reduced global DNA methylation and decreased transcript levels of Dnmt1, Dnmt3a, and Dnmt3b in skeletal muscle and adipose tissue. EC counteracted obesity-associated DNA methylation changes in skeletal muscle, restoring global methylation and Dnmt expression toward control levels, whereas effects in VAT were limited. EC increased mitochondrial DNA content. Discussion. In silico and enzymatic data suggest that EC may bind DNMT active sites and inhibit DNMT activity in a concentration-dependent manner, supporting a role for EC in obesity-related epigenetic remodeling, particularly in skeletal muscle. EC also increased relative mitochondrial DNA content in VAT and skeletal muscle despite no obesogenic diet effect on relative mitochondrial abundance, consistent with favorable mitochondrial modulation. In conclusion, EC is an epigenetic modulator and may have positive effects in obesity related dysfunctional tissues. Full article

Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications toward alcohol-mediated tissue injury remain incompletely defined. To address this gap, we performed a comprehensive integrative analysis of the publicly available circadian transcriptome datasets spanning genetic clock disruption, acute sleep deprivation, chronic high-fat diet feeding, and occupational shift work to systematically characterize the temporal regulation and disruption vulnerability of the major alcohol-metabolizing enzymes. Mouse tissue-cycling analyses revealed pronounced gene- and tissue-specific diurnal regulation, with Adh1 oscillating primarily in adipose tissues; Cyp2e1 and mitochondrial Aldh2 cycling broadly across kidney, aorta, lung, adrenal gland, and liver; and cytosolic Aldh1b1 being uniformly arrhythmic. In the liver, Cyp2e1 and Aldh2 exhibited robust ~24 h oscillations that peaked during the light/resting phase, while Adh1 showed inconsistent rhythmicity and Aldh1b1 remained arrhythmic. Notably, Cyp2e1 and Aldh2 rhythms persisted in Bmal1 knockout and Clock mutant livers under light–dark conditions, despite complete loss of core clock gene oscillations, yet were abolished in constant darkness, revealing that systemic zeitgeber cues can mask the loss of intrinsic clock function to maintain apparent rhythmicity in these metabolic genes. Systematic cross-paradigm comparison established a novel gene-specific vulnerability hierarchy. Aldh2 was found to be most disrupted by environmental and metabolic perturbations, with acute sleep deprivation eliminating its rhythmicity and temporal expression pattern and a Western-style high-fat diet inducing pronounced phase delays and rhythm loss relative to low-fat diet controls. Both disruptions paralleled alterations in hepatocyte nuclear factor 4α (Hnf4a), newly implicating HNF4α as a potential mediator of ALDH2 circadian instability. In humans, ALDH2 and CYP2E1 exhibited conserved but phase-inverted circadian rhythms across multiple tissues relative to mice, and, importantly, night-shift workers showed markedly dampened and phase-shifted ALDH2 rhythms in peripheral blood mononuclear cells, providing the molecular link between occupational circadian misalignment and impaired acetaldehyde detoxification. Collectively, our detailed and innovative analytical approach reveals gene- and tissue-specific circadian regulation of alcohol-metabolizing enzymes, identifies ALDH2 as uniquely vulnerable to circadian misalignment, underscores the importance of circadian timing for optimal hepatic detoxification and resistance to tissue injury, and suggests that monitoring circadian rhythms could help tailor individualized advice on alcohol consumption for shift workers and populations with irregular sleep schedules, informing precision medicine approaches for alcohol-related disorders. Full article

The protein kinase N family belongs to the AGC kinase group and contains three isozymes: PKN1, PKN2, and PKN3. Catalytic domains of PKNs share high sequence similarity, yet the proteins differ in tissue distribution, functions, and involvement in pathological processes. In particular, PKN3 has been implicated in tumor growth and metastatic progression, highlighting the need for isozyme-selective inhibitors as both research tools and therapeutic leads. Here, we report the rational design of selective PKN3 inhibitors based on distinctive structural features of this kinase. Two strategies were applied. First, the smaller threonine gatekeeper residue unique to PKN3 within the AGC group was exploited by derivatization of N-(2-aminoethyl)isoquinoline-5-sulfonamide (H-9) at position C8. Among the resulting compounds, a phenylamino-substituted derivative displayed the highest affinity, with a dissociation constant (K_D) of 23 nM and more than 1000-fold selectivity over protein kinase A. Second, bisubstrate-analog design was employed to enhance binding to basophilic AGC kinases through covalent attachment of a (d-Arg)₃-containing chain to H-9 derivatives. This approach yielded ARC-2603, which bound PKN3 with a K_D value of 0.2 nM and showed 5500-fold selectivity over PKAcα. The selectivity of ARC-2603 was further evaluated in a commercial panel of 397 protein kinases, which supported its utility as a highly selective PKN3 inhibitor. Full article

5a-reductase (5a-R) isozymes are essential for androgen metabolism and neurosteroid biosynthesis, linking endocrinology and neuropsychiatry. This systematic review, conducted in accordance with PRISMA 2020 guidelines, aimed to synthesize current evidence on the tissue distribution of SRD5A1, SRD5A2, and SRD5A3 and their implications in mental health. A systematic search of the PubMed, Scopus, and Web of Science databases up to February 2025 identified 257 articles, of which 83 met the inclusion criteria. SRD5A1 is broadly expressed in the liver, skin, and central nervous system, contributing to allopregnanolone synthesis; SRD5A2 is mainly restricted to androgen-dependent tissues, playing a key role in prostate development and alopecia; and SRD5A3 is associated with glycosylation processes and oncogenesis. Converging evidence suggests that impaired neurosteroidogenesis due to 5α-R inhibition may underlie vulnerability to anxiety, depression, and suicidality. While earlier epidemiological findings were heterogeneous, recent pharmacovigilance data have strengthened the evidence supporting this association. Pharmacovigilance and clinical reports show that a subset of patients treated with finasteride or dutasteride may experience persistent psychiatric and sexual adverse effects, known as post-finasteride syndrome. The current findings underscore the need for careful patient counseling, systematic monitoring, and further translational studies integrating genetics, neuroendocrine markers, and standardized psychiatric outcomes to identify individuals at risk and advance personalized medicine in this field. Full article

The existence of lignin in Physcomitrium patens has been controversial. However, cinnamyl alcohol dehydrogenase (CAD), the key enzyme in monolignol biosynthesis, has been identified with four gene members in P. patens. Despite the roles of PpCAD1 in moss architecture being proven in a previous study, the functions and molecular mechanisms of PpCAD4 remain largely unexplored in early terrestrial plants. This study aims to unravel this mystery via a comprehensive analysis of the transcriptome and metabolome of PpCAD4-overexpression (OE) lines compared with wild type (WT) under Botrytis cinerea treatment, firstly. A total of 475 and 1368 significantly differentially expressed genes in PpCAD4-OE lines compared to the wild type at 6 h and 12 h post-inoculation, which were predominantly enriched in pathways involving flavonoid, phenylpropanoid biosynthesis, and plant hormone signal transduction. Concurrently, metabolomic profiling revealed 160 and 114 differentially accumulated metabolites in PpCAD4-OE at the corresponding time points, with phenolic acids and flavonoids collectively constituting over 45% of these compounds. Furthermore, the MADS-box transcriptional factor PpMC6 negatively regulated PpCAD4 expression by yeast-one-hybrid and dual-luciferase assays. Finally, Catalase isozyme 2 (PpCAT2) and E3 ubiquitin-protein ligase (PpE3) were identified as interactive partners with PpCAD4, respectively, deducing that the increasing of reactive oxygen species might be promoted by PpCAT2 degradation through PpE3 after B. cinerea assault. Our results demonstrated that the essential roles and potential mechanisms of PpCAD4 are essential for defense against pathogens during the adaptation to land in moss. Full article

Traditional macrolide antimicrobials are inhibitors of cytochrome P4503A (CYP3A) in cattle liver. Monensin (MON), an ionophore with a narrow safety margin, undergoes CYP3A-dependent O-demethylation, and its incompatibility with macrolides is well recognized in livestock animals. This study evaluated the effects of newer macrolides—tilmicosin (TIL), tulathromycin (TUL), and gamithromycin (GAM)—on CYP3A-dependent metabolism in bovine liver microsomes and examined how these drugs influence MON hepatic metabolism. Molecular docking studies were also performed to predict their interactions with CYP3A enzymes. The CYP3A-dependent enzyme activity, testosterone 6β-hydroxylase, was inhibited in the presence of triacetyl-oleandomycin (used as a reference macrolide), as well as with MON. None of the other macrolides tested affected this enzymatic activity. All macrolides inhibited MON metabolism, but the extent of inhibition observed with triacetyl-oleandomycin was higher than that produced by TIL, TUL, and GAM. Molecular docking analyses indicated that triacetyl-oleandomycin and MON exhibited the highest binding affinities for the active site of CYP3A isozymes, compared with TIL, TUL, and GAM. The agreement between enzymatic data and in silico predictions indicates that TIL, TUL, and GAM are weaker inhibitors of CYP3A-mediated MON metabolism. The modest reduction in MON hepatic metabolism caused by these macrolides—commonly used in cattle feedlots—suggests a low likelihood of clinically relevant drug–drug interactions under typical dosing conditions. Full article

Background: Among the 15 human (h) carbonic anhydrase (CA; EC 4.2.1.1) isoforms, hCA IX and XII are particularly important due to their roles in tumor cell growth and survival, identifying them as promising targets for anticancer therapy. As a result, considerable effort has been directed toward the development of novel inhibitors that are highly selective for these isoforms. Methods: A library of twelve novel N-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carbothioamides 3 along with two new N-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carboxamide derivatives 5 were synthesized and their inhibition abilities were tested against four human carbonic anhydrase isozymes (hCA I, II, IX and XII) related to some global diseases including glaucoma, cancer and osteoporosis. Results: All compounds exhibited potent inhibition of the tested isoforms in the nanomolar range. Compound 3i showed the highest inhibition of hCA I activity but demonstrated poor selectivity toward the other isoforms. Compound 3h displayed superior selectivity for hCA II over hCA I (hCA I/II = 37) and exhibited 2.5-fold higher inhibitory activity compared to acetazolamide (AAZ). Among the tested compounds, 3l (K_i = 32.1 nM) demonstrated markedly improved selectivity for hCA IX over hCA I, II, and XII relative to the standard drug. Notably, compound 3a showed the most potent inhibition against hCA XII (K_i = 6.8 nM), comparable to AAZ, while exhibiting significantly greater selectivity over off-target isoforms and the other tumor-associated isozyme (hCA IX/XII = 20 versus hCA IX/XII = 4.5 for AAZ). Conclusions: The present study suggests potent lead compounds as selective hCA IX and XII inhibitors with anticancer activity. Full article

Manganese (Mn) is a crucial micronutrient for plants. The impaired function of the oxygen-evolving complex in Photosystem II (PSII) due to Mn deficiency is believed to result in the overproduction of reactive oxygen species and the induction of an enzymatic antioxidant system. In our study, we investigated the effects of progressive Mn deficiency (the difference in Mn content between the needles of control and Mn-deficient plants increased from 17-fold at the beginning of the experiment to 59-fold at the end) on the activities of superoxide dismutase (SOD), catalase, ascorbate peroxidase, and guaiacol peroxidase in the roots and needles of Scots pine seedlings. We found that the soluble protein content in plant organs under Mn deficiency was maintained at a level comparable to that of the control. Regardless of the severity of Mn deficiency, the needles of the Mn-deficient plants presented twofold lower SOD activity than the needles of the control plants. These differences were observed even when Mn deficiency did not negatively affect plant growth. Additionally, the total SOD activity in the needles of both plant groups was determined solely by the activity of the Cu/Zn-containing SOD isozymes. Compared with the control plants, Mn deficiency did not result in an increase in any of the studied H₂O₂-degrading enzymes in the needles of the seedlings. In contrast, the needles of the Mn-deficient plants presented a lower level of guaiacol peroxidase activity. Despite the inhibition of root growth, Mn deficiency led to changes in the balance of the enzymatic antioxidant system in plant roots. The data obtained suggest that the lack of activation of SOD and other antioxidant enzymes in Scots pine seedlings against the background of progressive Mn deficiency is due to the reduced ability of PSII to generate ROS under these conditions. Full article

The peptidylarginine deiminase (PAD) family includes five isozymes (PAD1–4 and PAD6) with unique tissue distributions and substrate specificities. These enzymes facilitate citrullination, a post-translational modification where positively charged arginine residues are converted into neutral citrulline residues in the presence of calcium ions. This process significantly changes protein properties, affecting molecular interactions, structural stability, and biological functions. Over the past six years (2019–2025), there has been significant progress in understanding PAD activity mechanisms and their therapeutic potential. Recent discoveries include the regulated nuclear translocation of PAD2, PAD4’s specific role in forming cancer extracellular chromatin networks (CECNs), and the development of next-generation inhibitors with greatly improved pharmacological profiles. PAD4 is crucial in forming neutrophil extracellular traps (NETs). Citrullination of histones H3 and H4 by PAD4 destabilizes chromatin, helping release DNA-protein networks as an antibacterial defense. However, excessive NET formation can contribute to autoimmune diseases and thrombosis. Similarly, the bacterial peptidylarginine deiminase from Porphyromonas gingivalis (PPAD)—the only known prokaryotic citrullinating enzyme—plays a key role. Working with R-gingipains, PPAD triggers pathological citrullination of host proteins, leading to immune tolerance breakdown and linking periodontal disease with systemic autoimmune disorders such as rheumatoid arthritis, atherosclerosis, and Alzheimer’s disease. Once thought to be a rare post-translational modification, citrullination is now understood as a vital regulatory mechanism in both normal physiology and disease, involving both internal processes of homeostasis and external mechanisms of bacterial pathogenesis. Full article

Post-translational modifications (PTMs) expand the structural diversity of proteins beyond the standard amino acids, influencing protein-protein interactions. Protein methylation, a prevalent PTM, involves the transfer of methyl groups from S-adenosylmethionine (SAM) to lysine and arginine residues. Arginine methylation is catalyzed by the Protein Arginine Methyltransferase (PRMT) family to yield mono- and dimethylarginine forms. PRMT1, the isozyme responsible for the majority of asymmetric dimethylation (ADMA) is implicated in various diseases, including cancer. Here, we report the synthesis and screening of a second-generation peptide library to identify novel PRMT1 substrates. The library, based on histone peptides, incorporated varying sequences of amino acids, facilitating substrate specificity studies. Screening identified 7 peptide sequences as exceptional PRMT1 substrates, which were confirmed by kinetic analysis. Consensus sequences revealed key recognition elements for PRMT1 catalysis, suggesting roles for small non-polar side chains and specific residues near the substrate arginine. Furthermore, we developed a peptide-based PRMT1 inhibitor by substituting the substrate arginine with a chloroacetamidine warhead. The inhibitor exhibited sub-micromolar inhibitory potency against PRMT1, surpassing previous peptide-based inhibitors. Our findings contribute to understanding PRMT1 substrate specificity and provide a scaffold for developing potent inhibitors targeting PRMT1 in diseases, including cancer. Full article