Search Results (10,601)

KRAS is one of the most frequently altered oncogenes in non-small cell lung cancer (NSCLC), playing a pivotal role in tumour initiation, progression, and therapeutic response. This review summarises the current understanding of the molecular mechanisms underlying KRAS-driven NSCLC, with particular emphasis on signalling pathways, genetic alterations, and their clinical implications. We discuss the spectrum of KRAS mutations and polymorphisms, highlighting their impact on disease biology, prognosis, and treatment outcomes. In addition, the review explores the contribution of epigenetic regulation to KRAS-mediated oncogenesis, focusing on the roles of non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as well as post-translational modifications of the KRAS protein, such as methylation, phosphorylation, ubiquitination, nitrosylation, and acetylation. Recent advances in the development of KRAS-targeted therapies are presented, including mutation-specific and pan-KRAS inhibitors. Furthermore, we discuss combination treatment approaches designed to overcome intrinsic and acquired resistance by targeting complementary signalling pathways or modulating the tumour microenvironment. Collectively, this review highlights the complexity of KRAS biology in NSCLC and underscores the importance of integrating molecular, epigenetic, and therapeutic insights to advance precision medicine and improve clinical outcomes. Full article

Background: Oxidative stress-mediated neuronal injury is critically involved in the pathogenesis of neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. Manganese dioxide (MnO₂), owing to its intrinsic reactive oxygen species (ROS)-scavenging capacity, has emerged as a promising neuroprotective candidate; however, the underlying molecular mechanisms remain insufficiently defined. Methods: Bovine serum albumin-templated MnO₂ nanoparticles (BSA-MnO₂ NPs) were synthesized, and their protective effects were evaluated in H₂O₂-treated PC12 cells. Results: BSA-MnO₂ NPs significantly inhibited H₂O₂-induced reductions in cell viability, ROS overproduction, and mitochondrial membrane potential disruption. Mechanistically, H₂O₂ increased both LC3-II and p62 levels, indicating impaired autophagic flux. Activation of autophagy by serum starvation alleviated H₂O₂-induced injury, whereas chloroquine exacerbated cellular damage and abolished the protective effects of BSA-MnO₂ NPs, suggesting that the restoration of autophagy contributes to BSA-MnO₂ NPs-mediated neuroprotection. Further analysis showed that BSA-MnO₂ NPs enhanced Akt phosphorylation, while LY294002, a PI3K inhibitor, suppressed Akt activation, disrupted autophagy regulation, and eliminated their neuroprotective effects. In contrast, chloroquine did not affect Akt phosphorylation, indicating that PI3K/Akt signaling acts upstream of autophagy regulation. Conclusions: Collectively, these findings demonstrate that BSA-MnO₂ NPs protect PC12 cells against H₂O₂-induced oxidative injury by restoring autophagy through the PI3K/Akt signaling pathway, highlighting a potential role of BSA-MnO₂ NPs in the treatment of oxidative-stress-related neurodegenerative disorders. Full article

Type 2 diabetes mellitus (T2DM) is a major global health challenge, with insulin resistance (IR) and islet dysfunction as its core pathophysiology. Current glucose-lowering agents, including insulin secretagogues, insulin sensitizers, DPP–IV inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists, effectively control blood glucose and may partly improve β-cell function indirectly, but they do not directly target the functional defects of pancreatic β cells. Developing drugs that precisely modulate islet function is therefore a key direction. Natural products, with their structural diversity, established glucose-lowering activity, and derivation from medicinal plants with long clinical use, have become an important source of lead compounds for drugs targeting these mechanisms. The main pathways through which natural products act include: (1) promoting insulin secretion through direct and indirect secretagogue mechanisms (modulating ion channels, metabolic enzymes, incretin signaling); (2) preserving β-cell function and mass by maintaining the differentiated phenotype, promoting regeneration, alleviating oxidative stress, inhibiting apoptosis and pyroptosis, attenuating inflammation, and suppressing hIAPP toxic aggregation and endoplasmic reticulum stress; and (3) other pathways with incompletely elucidated mechanisms that also contribute to islet protection. This article delineates these molecular mechanisms and highlights the limited ability of current agents to directly restore and protect β-cell function. It provides a theoretical basis for developing novel drugs that integrate glycemic control with islet restoration based on natural lead compounds, and offers a framework for further mechanistic studies. In addition, it encourages the exploration of unidentified active constituents and unique pathways, while also addressing challenges such as target identification and structure–activity relationships. Full article

Background: Acute compartment syndrome (ACS) is a critical orthopedic emergency where increased pressure in a limb compartment leads to muscle ischemia, necrosis, and lasting dysfunction. While fasciotomy is the standard treatment, it often results in complications like infection and nerve damage, underscoring the need for effective non-surgical therapies to manage the inflammation causing tissue damage. Peripheral nerve block (PNB) with ropivacaine is clinically used for analgesia, but whether it can serve as a disease-modifying adjunct intervention for ACS beyond pain control remains unexplored. Objective: This study examined the potential of PNB utilizing ropivacaine to enhance outcomes in ACS and explored the underlying mechanisms related to macrophage polarization. We aimed to distinguish two unresolved questions: (1) whether ropivacaine-based PNB confers tissue-protective effects in ACS independent of analgesia; (2) what signaling pathway mediates ropivacaine-driven macrophage phenotypic switch under ACS-relevant inflammatory conditions. Methods: Using rats, an ACS model was established, with the animals being randomly allocated to five different groups: Control, ACS, sciatic PNB, femoral PNB, and combined PNB. The study assessed functional outcomes, histopathological changes, levels of inflammatory markers (interleukin-6 (IL-6), C-reactive protein (CRP), and markers of macrophage polarization (CD86, CD206). In parallel, RAW264.7 macrophages stimulated with LPS and IFN-γ were treated with ropivacaine (1–10 μg/mL), and M1/M2 markers, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), migratory capacity, and cytotoxicity were assessed. Differentially expressed genes and enriched pathways were identified through RNA sequencing, followed by mechanistic validation of JAK-STAT signaling using Western blotting, immunofluorescence, immunohistochemistry, and rescue experiments with the JAK2 inhibitor AG490. Results: PNB significantly improved all functional and histological parameters in ACS rats, with combined blockade demonstrating the greatest efficacy. Ropivacaine at 5 μg/mL promoted M2 macrophage polarization, evidenced by upregulated CD206 and arginase-1 alongside downregulated CD86 and iNOS, while reducing pro-inflammatory cytokine production without cytotoxicity. Ropivacaine also suppressed macrophage migration. Among 83 differentially expressed genes, RNA sequencing pinpointed JAK-STAT as the pathway with the highest level of enrichment. Mechanistically, ropivacaine activated JAK2-STAT3, reflected by increased p-JAK2/JAK2 and p-STAT3/STAT3 ratios. AG490 completely reversed ropivacaine-induced JAK-STAT activation, M2 polarization, cytokine suppression, and migratory inhibition in vitro, and similarly abrogated PNB-mediated functional recovery and histological protection in vivo. Conclusions: In vitro, ropivacaine directly promoted macrophage M2 polarization via JAK-STAT activation. In vivo, ropivacaine-based PNB ameliorates ACS, which may involve both direct immunomodulatory effects of ropivacaine and indirect biological consequences of peripheral neural blockade. This study provides the first pre-clinical proof-of-concept that ropivacaine PNB can act as an adjunctive disease-modifying strategy for ACS (beyond analgesia), and identifies macrophage JAK2-STAT3 as the critical molecular cascade responsible for this immunomodulatory effect. This identifies a readily translatable adjunctive strategy for ACS and establishes JAK-STAT as a potential pharmacological target for compartment syndrome-associated inflammation. Full article

Transient receptor potential vanilloid channel 3 (TRPV3) is a keratinocyte-expressed ion channel that regulates calcium signaling and thymic stromal lymphopoietin (TSLP) production, contributing to pruritic inflammatory skin diseases. Although avicularin (AVC), a flavonoid from Polygonum aviculare L., and senegenin (SNG), the bioactive aglycone of Polygala tenuifolia Willd., possess anti-inflammatory properties, their effects on TRPV3-associated signaling remain unknown. A natural product library was screened for nitric oxide (NO) production in carvacrol-stimulated human keratinocytes. Following primary screening and secondary evaluation of TRPV3 and TSLP expression, AVC and SNG were selected for further study and subsequently evaluated by molecular docking, calcium imaging, quantitative real-time PCR, immunocytochemistry, and pathway inhibition assays. AVC and SNG showed favorable predicted docking poses at both TRPV3 docking sites and significantly attenuated carvacrol-induced calcium-dependent fluorescence responses in TRPV3-expressing cells. Both compounds reduced TRPV3 and TSLP expression at the mRNA and protein levels and attenuated the nuclear translocation of phospho-Nuclear Factor of Activated T Cells 2 (NFATC2) and phospho-p50. Co-treatment with NFAT or Nuclear Factor Kappa B (NF-κB) inhibitors produced no additional suppression, consistent with convergence of AVC/SNG-associated effects with NFAT/NF-κB signaling. Collectively, these findings support further investigation of AVC and SNG as candidate modulators of TRPV3-associated inflammatory signaling in keratinocytes. Full article

Cutaneous melanoma remains a global health challenge. Although BRAF/MEK-targeted therapies and immune checkpoint inhibitors (ICIs) have improved outcomes in advanced disease, durable responses remain difficult to achieve for most patients. Therapeutic resistance represents the central barrier to long-term disease control. This review comprehensively examines the molecular and immunologic mechanisms underlying melanoma resistance and integrates these insights with emerging pharmaceutical strategies designed to overcome them. We explore the genetic landscape of melanoma, including oncogenic alterations in BRAF, NRAS, NF1, CDKN2A, and PTEN, and explain how dysregulation of the MAPK and PI3K/AKT/mTOR signaling axes drives therapeutic escape. Phenotypic plasticity is discussed as a critical epigenetic driver of drug tolerance. The tumor microenvironment (TME) is examined as an active co-conspirator in resistance, encompassing immunosuppressive cell populations, cancer-associated fibroblasts, and metabolic competition. Resistance mechanisms to targeted therapy, including MAPK reactivation, bypass signaling, transcriptional reprogramming, and metabolic rewiring, are reviewed alongside tumor-intrinsic and tumor-extrinsic mechanisms of ICI resistance. Emerging therapeutic strategies are surveyed, including next-generation RAF and ERK inhibitors, dual-pathway blockade, and metabolic therapies targeting oxidative phosphorylation. Innovations in molecular imaging, liquid biopsy, and artificial intelligence-driven biomarker discovery are highlighted as pivotal tools for real-time resistance monitoring and adaptive treatment. By linking mechanistic insights with translational advances, this review advocates for combination strategies and adaptive clinical frameworks to achieve more durable disease control in melanoma. Full article

Human immunodeficiency virus (HIV) is one of the viruses that has co-evolved within human populations for a considerable time. With the evolution of new drug-resistant HIV strains, the necessity to discover novel drugs has become an issue of great concern, especially those that have increased binding affinities and inhibitory activity towards RT enzymes. This study used an in silico approach to identify potential HIV-RT inhibitory candidates from Origanum vulgare (oregano). An initial in silico screening of approximately 820 compounds was conducted, and based on molecular docking-derived binding energy scores, four compounds (IMPHY000687, IMPHY007084, IMPHY004619, and IMPHY012021), with docking scores of −9.42, −9.32, −9.24, and −9.23 kcal/mol, respectively, were selected as the top-ranked phytocompounds and were subsequently validated using multiple computational approaches. These compounds were geometrically optimized using quantum-chemical calculations, and detailed interaction analyses were performed using a redocking procedure. Reproducibility of the dynamic behavior was evaluated by carrying out independent replica molecular dynamics simulations for 300 ns each for all complexes. The ligand-dependent conformational dynamics were identified using RMSD and RMSF analyses, along with variations in positional changes during simulation times. PCA and FEL analyses helped in identifying the conformations sampled by the system under study. In addition, QM/MM calculations provided complementary information on the electronic characteristics of the individual protein–ligand systems. Machine learning-based quantitative structure–activity relationship (QSAR) prediction of experimentally validated HIV-RT inhibitors was applied to predict inhibitory potency, yielding predicted pIC50 values for the selected phytochemicals compared with the reference molecule. All in all, comprehensive computational analyses have ranked these phytochemicals as HIV-RT inhibitors that need further experimental verification. Full article

Pometia pinnata J.R. Forst. & G. Forst. is traditionally used throughout tropical Asia and the Pacific to manage diabetes-associated hyperglycemia. However, the metabolites responsible for its α-glucosidase inhibitory activity (AGI) remain poorly characterized. This study aimed to identify putative AGI-associated metabolites from P. pinnata stem bark through metabolomics-based prioritization and tentative annotation using untargeted LC–HRMS, followed by molecular docking to assess their interactions with α-glucosidase. Thirty ethyl acetate–methanol gradient fractions were analyzed by orthogonal partial least squares (OPLS) to prioritize LC–HRMS features associated with AGI activity, followed by molecular docking of the tentatively annotated metabolites against Saccharomyces cerevisiae α-glucosidase (3A4A) and human maltase-glucoamylase (3TOP). The 75% ethyl acetate in methanol fraction showed the strongest AGI, with an IC₅₀ of 5.53 μg/mL. Five AGI-associated metabolites, namely scopoletin, 3,4-dihydroxybenzaldehyde, fisetin, 4-methoxycinnamic acid, and lindetannin, were tentatively annotated in P. pinnata stem bark based on LC-HRMS/MS data. To the best of our knowledge, these annotations have not previously been reported in P. pinnata stem bark. Among these candidates, fisetin showed the most favorable binding interactions with both target enzymes. Metabolomics-guided isolation, followed by NMR analysis, confirmed the structure of scopoletin, although the isolated compound showed weak AGI activity (IC₅₀ > 200 μg/mL). The marked difference between the parent fraction and isolated scopoletin indicates that scopoletin alone is unlikely to account for the observed activity and that other constituents may contribute. Nevertheless, this study provides a promising metabolomics-guided framework for prioritizing and tentatively annotating candidate AGI-associated metabolites in the stem bark of P. pinnata. Full article

Background: Bicuspid aortic valve disease (BAVD) is the most frequent congenital heart disease, occurring either as an isolated lesion or in association with other congenital cardiovascular malformations, with variable patterns of progression and risk of valvular and vascular complications. Studies addressing pediatric bicuspid aortopathy are still in their infancy. This narrative review aims to provide a comprehensive perspective on the current scientific evidence regarding BAVD-associated aortopathy in pediatric patients, underscoring multiple challenges in initial diagnosis, long-term surveillance, and therapeutic decision-making, and focusing on the potential roles of circulating biomarkers and advanced multimodal imaging tools that may improve individualized risk stratification. Methods: Despite the narrative design of this review, a structured search of the current available literature was performed to identify studies addressing pediatric BAV, associated aortopathy, biomarkers, vascular remodeling, and multimodal imaging. Priority was given to pediatric cohorts, longitudinal studies, consensus documents, and contemporary guidelines. The search was conducted in the online databases PubMed/Medline and Web of Science for English-language original articles published in the last 10 years, up to May 2026. We used the following main terms: “Bicuspid Aortic Valve Disease” [MeSH], “Aorta” [MeSH], “Infant” [MeSH], “Child” [MeSH], “Adolescent” [MeSH], combined by Boolean operators with secondary keywords: “pathogenesis”, “mechanism”, “progression”, “multimodal imaging”, “echocardiography”, “cardiovascular magnetic resonance imaging”, “computed tomography”, “circulating biomarkers”. The retrieved studies were screened for eligibility using previously established inclusion and exclusion criteria. A total of 63 studies were included in the analysis for this narrative review. Results: Two main theories underpin the etiopathogenesis of aortopathy associated with the bicuspid aortic valve, positing that genetic factors predispose the aortic wall to remodeling in an abnormal hemodynamic environment. Embryological development and dysregulation of molecular and cellular structures are also intertwined during the formation and progression of the aortic valve with two semilunar cusps, resulting in consequent alterations in the aortic wall’s architectural organization. Advances in molecular studies have highlighted circulating biomarkers with potential utility in predicting aortopathy, as they are involved in extracellular matrix remodeling, endothelial dysfunction, and aortic valve calcification, including matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), transforming growth factor-β (TGF-β), and microRNAs. In addition, multimodal imaging techniques have emerged as essential tools for assessing the morphology and function of cardiovascular structures, particularly aortic biomechanical properties and hemodynamic abnormalities, at the time of initial diagnosis and during regular monitoring. Taken together, blood biomarkers and imaging parameters of aortic remodeling and flow disturbances might gain increasing prognostic value in pediatric BAVD-associated aortopathy. However, larger longitudinal studies are required for clinical validation beyond research settings. Although guidelines on the management of BAVD are available for adults, they are not entirely applicable to children, who are undergoing continuous somatic growth that affects diagnostic possibilities and therapeutic options. Conclusions: Despite growing literature in the realm of BAVD and related conditions, the management of pediatric patients remains challenging in daily clinical practice, as adult guidelines cannot be completely applied to children. Given the heterogeneity and complexity of pathogenic mechanisms, clinical presentations, natural history, and outcomes, future research is warranted to explore the progression profiles of valvular and vascular disorders associated with BAV in children and to achieve an optimal approach to pediatric bicuspid aortopathy. Full article

Alcoholic liver injury (ALI) represents a significant global health burden with limited therapeutic options. Xanthoxylin, a natural flavonoid compound, has demonstrated potential hepatoprotective properties, yet its underlying molecular mechanisms against ALI remain poorly elucidated. This study employed an integrated strategy combining network pharmacology, molecular docking, molecular dynamics (MD) simulations, and in vitro experimental validation to systematically investigate the protective mechanisms of xanthoxylin against ALI. Network pharmacology screening identified 52 intersection targets between xanthoxylin and ALI, with the top 10 core targets comprising ALB, PPARG, BCL2, PTGS2, ESR1, HIF1A, EGFR, HSP90AA1, GSK3B, and PARP1. GO enrichment analysis highlighted mitochondrion and mitochondrial outer membrane among the top 10 cellular component (CC) terms. KEGG pathway analysis revealed PI3K-Akt signaling within the top 10 pathways. Molecular docking suggested potential binding of xanthoxylin to the key targets. Subsequent MD simulations further confirmed the formation of stable complexes between xanthoxylin and EGFR, PPARG, and PTGS2. In vitro, xanthoxylin significantly ameliorated ethanol-induced HepG2 cell injury, attenuated TC and TG elevations, suppressed mitochondrial ROS accumulation, and enhanced SOD activity. Mechanistically, xanthoxylin upregulated HSP90, p-EGFR, EGFR, p-AKT, AKT, and PPARG protein expression, and suppressed the expression levels of PTGS2. Erlotinib, an EGFR inhibitor, reversed the cytoprotective effects of xanthoxylin. Xanthoxylin protects against alcoholic liver injury through regulating the EGFR/AKT pathway, with concurrent modulation of PPARG and PTGS2. These findings provide compelling evidence for xanthoxylin as a promising therapeutic candidate for ALI and establish a foundation for subsequent preclinical development. Full article

COVID-19, caused by SARS-CoV-2, remains a global health challenge because of viral evolution and immune escape. Although current therapies primarily target viral entry and replication, agents that directly interfere with the Spike receptor-binding domain (S-RBD) remain limited. Here, we combined virtual screening with biological validation to identify compounds capable of interfering with S-RBD function. A total of 3014 compounds from a customized drug library were screened by molecular docking. Candidate binding and functional activity were subsequently evaluated using cellular thermal shift assays, surface plasmon resonance, immunoprecipitation, immunofluorescence, and pseudovirus-entry assays against 2019-nCoV, Delta, and Omicron pseudoviruses. DOTAP chloride (K_D = 49.94 μM), cefotiam hexetil hydrochloride (K_D = 142.26 μM), melittin (K_D = 34.98 μM), and teicoplanin (K_D = 73.58 μM) showed detectable binding to the S-RBD and inhibited Spike-mediated pseudovirus entry. Molecular docking suggested that these interactions were mediated by potential binding modes involving hydrogen bonds and π-interactions. The compounds interfered with S-RBD/hACE2 colocalisation and inhibited pseudovirus entry with variant-dependent efficacy. DOTAP chloride (25 μM) inhibited entry of the 2019-nCoV and Omicron pseudoviruses, whereas the other three compounds showed activity across the tested variants. These findings identify four compounds with RBD-binding and entry-inhibition properties for further development as entry inhibitors. Full article

The rising global prevalence of hyperuricemia has intensified the search for natural xanthine oxidase (XO) inhibitors from food-grade botanicals. This study screened leaf extracts from four plant species for XO inhibitory activity and identified raspberry leaf as the most potent source. Among seven extraction and pre-treatment methods, ultrasound-assisted extraction (UAE) outperformed conventional decoction and all alternatives. Box–-Behnken response surface methodology optimized UAE parameters to 70 °C, 50 min, and a solid-to-liquid ratio of 1:20 g/mL, yielding an extract with 97.77 ± 0.08% XO inhibition and an IC₅₀ of 0.3433 mg/mL—a 5.34-fold potency gain over decoction. Kinetic characterization established a reversible mixed-type inhibition mechanism (K_i = 0.147 mg/mL), alongside parallel improvements in DPPH, ABTS, and hydroxyl radical scavenging. Widely targeted UHPLC-MS/MS metabolomics identified 2987 metabolites; network pharmacology and molecular docking revealed that the origin of XO inhibition potentially involves terpenoids and coumarins—not the flavonoid and polyphenol fractions conventionally assumed—with dihydroactinidiolide, 7-hydroxy-8-methoxycoumarin, and piperlongumine as the candidate active constituents. These results position UAE-optimized raspberry leaf extract as a promising natural functional ingredient for hyperuricemia management and expand the phytochemical scope of plant-derived XO antagonists beyond flavonoids. Full article

Cercospora beticola, the causal agent of Cercospora leaf spot (CLS), is a major pathogen affecting beet (Beta vulgaris) worldwide. Rapid and accurate detection is critical for effective disease control. This study validated a diagnostic framework combining portable quantitative PCR (qPCR) and laboratory-based digital droplet PCR (ddPCR) assays to detect and quantify C. beticola in leaves, seeds, and soil-associated crop residues. We used two portable qPCR systems (Biomeme Franklin^® Three9 and Hyris bCUBE^™) for in-field diagnostics, and ddPCR (Bio-Rad Laboratories) for laboratory analysis. Two rapid DNA extraction protocols, the Sigma-Aldrich REDExtract-N-Amp Plant PCR Kit (brief incubation at 95 °C) and the BN QuickPick Plant DNA Kit (magnetic-bead-based), were evaluated. The optimized portable qPCR assays achieved detection limits of 1 pg μL⁻¹, PCR efficiencies of 96–102%, and R² > 0.98. The ddPCR assay enabled accurate and absolute quantification even at low target concentrations and was resilient to common PCR inhibitors. Both methods proved robust in complex environmental matrices, with a detection threshold of 1% in infected residue soil. The framework’s sensitivity, specificity, and portability support timely on-site CLS diagnosis and informed management. This integrated approach advances portable molecular diagnostics and provides a platform for future field-ready disease surveillance and sustainable crop protection. Full article

Proteolytic processing of viral polyproteins by virally encoded proteases is essential for the replication of many RNA viruses, including retroviruses and coronaviruses, which are two of the best characterized model systems discussed in this review. These proteases are initially synthesized as polyprotein precursors that possess intrinsic, albeit comparatively low, catalytic activity and undergo tightly regulated autoprocessing to generate the mature enzymes required for viral replication. Accumulating evidence indicates that protease precursors are catalytically and mechanistically distinct from their mature counterparts, exhibiting unique biochemical properties and regulatory features that govern their activation. Therefore, precursor autoprocessing represents a critical checkpoint in viral maturation and an attractive, yet largely unexplored, target for antiviral intervention. This review examines the current understanding of the molecular mechanisms underlying precursor autoprocessing of HIV-1 protease and coronavirus main protease, with particular emphasis on the structural, biochemical, and regulatory features that distinguish precursor enzymes from their mature forms. It also highlights the experimental challenges associated with studying these highly dynamic and conformationally heterogeneous precursors, as well as recent advances in functional screening platforms that have enabled the discovery of proof-of-concept small molecules targeting precursor autoprocessing. Notably, several hit compounds retain activity against HIV-1 variants resistant to clinically approved protease inhibitors (PIs), while also inhibiting the wild-type strain. Together, these findings suggest that protease precursor autoprocessing may serve as a promising antiviral target and provide a conceptual framework for the development of next-generation therapeutics that complement existing mature-protease inhibitors. Full article

Background/Objectives: MEK inhibitors (selumetinib, mirdametinib) are the only approved class of targeted therapy for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN), producing partial responses in a substantial proportion of patients (up to 63.6% in adults; objective response rate 19.7% versus 5.4% with placebo in the KOMET trial). Responses, however, are rarely complete or durable, and in malignant peripheral nerve sheath tumor (MPNST) single-agent MEK inhibition is clinically ineffective. Mechanisms of escape from MEK inhibition in these tumors remain poorly characterized and are reported in the literature as isolated primary studies without an integrative analysis. The aim of this review was to systematize both the established molecular mechanisms of resistance to MEK inhibitors in PN and MPNST and the biologically plausible candidate mechanisms extrapolated from other RAS-driven malignancies. Methods: This is a narrative review. A structured search was performed in PubMed, PubMed Central, NCBI Bookshelf, and Scopus, supplemented by clinical practice guidelines and regulatory documents; it covered publications up to 31 May 2026 and was updated in August 2026. Ninety-six sources are cited, and their composition by publication type is reported; record counts at the intermediate screening steps were not maintained, and no PRISMA flow diagram is presented. Results: Mechanisms were classified within a convergent framework into six categories: reactivation of MAPK signaling within the cascade; parallel (bypass) reactivation through receptor tyrosine kinases and adjacent inputs; epigenetic and transcriptional rewiring; cell survival programs; the tumor microenvironment and immune evasion; and intratumoural heterogeneity. Each mechanism was then graded along two independent axes—the strength of evidence that it confers resistance in PN or MPNST (E1–E3) and its therapeutic tractability (T1–T3)—and annotated with the entity and model constituting its evidence source. Conclusions: Resistance to MEK inhibition in PN and MPNST is convergent rather than mechanism-unique. The principal limitation of the field is the near-absence of clinical resistance data from patients progressing on MEK inhibitors; prospective molecular monitoring, rational combination trials, and mechanism-stratifying biomarkers are the priorities. Full article