Search Results (1,103)

Background/Objectives: Neovascularization, defined as the sprouting of new blood vessels from pre-existing vasculature, is a critical pathological feature in ocular diseases such as pathological myopia and represents a leading cause of corneal vision loss. Vascular endothelial growth factor A (VEGFA) plays a pivotal role in endothelial cell proliferation, migration, survival by anti-apoptotic signaling, and vascular permeability. Dysregulation of VEGFA is closely linked to pathological neovascularization. Exosomes, nanosized phospholipid bilayer vesicles ranging from 30 to 150 nm, have emerged as promising gene delivery vehicles due to their intrinsic low immunogenicity, superior cellular uptake, and enhanced in vivo stability. This study aimed to investigate whether highly purified mesenchymal stem cell (MSC)-derived exosomes loaded with VEGFA siRNA labeled with FAM can effectively suppress pathological corneal neovascularization (CNV) via targeeted cellular transduction and VEGFA inhibition. Furthermore, we examined whether the therapeutic effect involves the modulation of the PI3K–Akt–Caspase-3 signaling axis. Methods: Exosomes purified by chromatography were characterized by electronmicroscopy, standard marker immunoblotting, and nanoparticle tracking analysis. In vitro, we assessed exosome uptake and cytoplasmic release, suppression of VEGFA mRNA/protein, cell viability, and apoptosis. In a mouse CNV model, we evaluated tissue reach and stromal retention after repeated intrastromal injections; anterior segment angiogenic indices; CD31/VEGFA immunofluorescence/immunoblotting; phosphorylated PI3K and Akt; cleaved caspase-3; histology (H&E); and systemic safety (liver, kidney, and spleen). Results: Exosomes were of high quality and showed peak efficacy at 48 h, with decreased VEGFA mRNA/protein, reduced viability, and increased apoptosis in vitro. In vivo, efficient delivery and stromal retention were observed, with accelerated inhibition of neovascularization after Day 14 and maximal effect on Days 17–19. Treatment reduced CD31 and VEGFA, decreased p-PI3K and p-Akt, and increased cleaved caspase-3. Histologically, concurrent reductions in neovascularization, inflammatory cell infiltration, and inflammatory epithelial thickening were observed, alongside a favorable systemic safety profile. Conclusions:VEGFA siRNA-loaded exosomes effectively reduce pathological CNV via a causal sequence of intracellular uptake, cytoplasmic release, targeted inhibition, and phenotypic suppression. Supported by consistent PI3K–Akt inhibition and caspase-3–mediated apoptosis induction, these exosomes represent a promising local gene therapy that can complement existing antibody-based treatments. Full article

KRAS alterations are a hallmark of pancreatic ductal adenocarcinoma (PDAC) found in >90% of tumors. This review examines the historical evolution of the understanding of RAS and its central role in PDAC biology. We summarize the various downstream effectors, feedback loops, and resistance mechanisms that play a pivotal role in PDAC oncogenesis. Our review explores the early development of covalent inhibitors of KRAS G12C and efforts at specific inhibition of other codons and newer approaches of targeted protein degradation. We subsequently summarize the development of panRAS inhibitors and allosteric and switch-region targeting before focusing on rational therapeutic blockade of crosstalk and upstream signaling, with attention to synthetic lethality approaches transitioning from preclinical to early-phase in-human clinical trials. This review elaborates on ongoing KRAS-specific siRNA research and evolving KRAS-directed immunotherapies. We conclude by outlining the current KRAS clinical trial landscape and future areas of investigation. Full article

Epithelial ovarian cancer (EOC) represents the most lethal malignancy arising from the female reproductive tract, largely due to the clinical challenge of chemotherapy resistance. Recent studies indicate that ferroptosis—a distinct form of programmed cell death driven by iron accumulation and lipid peroxidation, could potentially exploit a vulnerability in chemoresistant cancer cells. Here, we identify MED12 as a critical regulator of ferroptosis sensitivity in EOC through modulation of the YAP–TEAD1 signaling pathway. Using CRISPR/Cas9-mediated knockout and rescue experiments in EOC cell lines, we demonstrate that MED12 deficiency significantly enhances sensitivity to ferroptosis inducers (RSL3 and Erastin), as evidenced by reduced IC50 values. Transcriptomic and chromatin accessibility analyses reveal that MED12 loss activates YAP signaling through TEAD1 upregulation, increasing chromatin accessibility at YAP–TEAD1 target loci and elevating the expression of downstream effectors CYR61 and CTGF. Pharmacological inhibition of YAP with verteporfin or siRNA-mediated TEAD1 knockdown reverses ferroptosis sensitivity in MED12-deficient cells, confirming pathway specificity. These findings establish MED12 as a modulator of the YAP–TEAD1–ferroptosis axis and suggest that targeting this pathway could overcome chemoresistance in MED12-deficient EOC. Our work provides a mechanistic foundation for exploiting ferroptosis induction as a therapeutic strategy in ovarian cancer. Full article

This study evaluates and compares the protective effects of several type II taste receptor (T2R) agonists against LPS (lipopolysaccharide)-induced inflammatory damage in BEAS-2B cells, focusing on their action via an α-gustducin (encoded by GNAT3)-dependent signaling pathway that leads to NF-κB inhibition. To investigate gene expression, mRNA levels of target inflammatory cytokines and T2R subtypes were quantified by qRT-PCR. Cytotoxicity assessment of LPS and bitter agonists was conducted using the CCK-8 assay. The activation status of the NF-κB pathway was examined by Western blot analysis of total and phosphorylated forms of p65 and IκB. Finally, the specific and essential role of GNAT3 was definitively validated through siRNA-mediated gene knockdown. LPS treatment induced significant upregulation of IL-6 and IL-8 mRNA, along with increased phosphorylation of p65 and IκB in BEAS-2B cells. A direct, parallel comparison of the bitter taste agonists PTC (phenylthiourea), QN (quinine), CPD (carisoprodol), and LK (chloroquine) revealed their capacity to upregulate specific T2R subtypes, suppressing inflammatory mediator release and NF-κB activation. Critically, upon GNAT3 silencing, the inhibitory effects of all tested agonists on p-p65/p65 and p-IκB/IκB ratios were significantly attenuated, without altering total p65 or IκB abundance. This provides direct genetic evidence that GNAT3 is specifically required for mediating the anti-inflammatory effects elicited by these T2R agonists. Multiple bitter receptor agonists exert anti-inflammatory effects on airway epithelial cells in a GNAT3-dependent manner. Our study advances the field by systematically comparing agonist efficacy and establishing the indispensable role of GNAT3 within the anti-inflammatory signaling cascade triggered by T2R agonists, thereby revealing a refined mechanistic insight and potential therapeutic target for inflammatory lung diseases. Full article

Keratin, a core structural protein in epithelial cells, is essential for maintaining epithelial tissue integrity. Numerous studies have confirmed its critical role in proliferative disorders, including lung/liver cancer, idiopathic pulmonary fibrosis (IPF), and hepatic fibrosis (HF). Post-translational modification (PTM) regulates protein activity, and keratin undergoes phosphorylation, acetylation, and methylation—modifications that modulate fibrosis and cancer progression by regulating relevant signaling pathways. However, how these modifications reshape keratin’s structure and function in these diseases remains understudied, underscoring the necessity for a systematic review. This review first summarizes keratin’s classification, physiological functions, and roles in epithelial cells, then focuses on the physiological significance of keratin modifications in fibrosis and cancer, while dissecting the molecular mechanisms by which keratin PTMs drive disease progression to address the knowledge gap regarding modification-related keratin changes. Elucidating the mechanisms of keratin and its PTMs is pivotal for understanding disease progression and developing targeted therapies; meanwhile, keratin-targeted strategies—such as keratin siRNAs and small-molecule compounds that regulate keratin expression or modification—have shown therapeutic potential. In summary, this review synthesizes current research findings and provides novel insights for the treatment of fibrosis and cancer. Full article

Background: Acacetin, a naturally occurring flavone present in various plants, is known as a promising drug candidate for cardiovascular disorders. Our previous study demonstrated that acacetin ameliorates atherosclerosis through endothelial cell protection; however, its pharmacological effects on vascular smooth muscle cells (VSMCs) remain unexplored. This study investigates the therapeutic potential of acacetin against lysophosphatidylcholine (LysoPC)-induced VSMC injury and elucidates the underlying molecular mechanisms. Methods and Results: Multiple biochemical techniques were employed in the present study. The results showed that acacetin significantly attenuated LysoPC-induced apoptosis and reactive oxygen species (ROS) generation in cultured VSMCs. Western blot analysis revealed that the cytoprotection of acacetin was associated with upregulated expression of antioxidant defense proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), NADPH quinone oxidoreductase 1 (NQO-1), and superoxide dismutase 1 (SOD1). Nrf2 silencing completely abolished these protective effects. Mechanistically, siRNA-silencing of Sirtuin 1 (Sirt1) abrogated acacetin-induced modulation of the Nrf2/Keap1/p62 signaling. In vivo validation using aortic tissues from high-fat-diet-fed ApoE^−/− mice confirmed that acacetin effectively suppressed VSMC apoptosis and ROS overproduction associated with restoring the downregulated Sirt1 expression levels. Conclusions: These findings establish a novel mechanistic paradigm wherein acacetin confers protection against LysoPC-induced VSMC apoptosis and oxidative stress through Sirt1-dependent activation of the Nrf2/p62 signaling pathway, suggesting that acacetin is a promising therapeutic drug candidate for atherosclerotic plaque stabilization. Full article

Multiple myeloma (MM) is a challenging hematologic malignancy characterized by clonal plasma cell proliferation, often leading to significant morbidity and mortality worldwide. Despite advances in chemotherapy and CAR-T therapies, MM remains incurable due to tumor heterogeneity, immune evasion, and microenvironment remodeling—exacerbated by toxicities like cytokine release syndrome and myelosuppression. This urgent unmet need demands innovative strategies. In this review, we assess cutting-edge RNA-based therapeutics for MM modulation, drawing on preclinical and clinical evidence on modalities including mRNA vaccines, small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and microRNA (miRNA) mimics/inhibitors. We further explore RNA-engineered cell therapies, such as transient CAR-T platforms and lipid nanoparticle-delivered systems targeting the bone marrow niche. By integrating these insights, we underscore RNA technologies’ transformative potential to achieve durable remissions, overcome resistance, and reduce costs—paving the way for personalized, safer treatments in refractory MM. Full article

Although oxidants are known to be deleterious for cellular homeostasis by oxidizing macromolecules like DNA or proteins, they are also involved in signaling processes essential for cellular proliferation and survival. Here, we investigated the role of superoxide anion (O₂⁻) and hydrogen peroxide (H₂O₂) homeostasis for the proliferation and survival of classical Hodgkin’s lymphoma (cHL) cell lines. Inhibition of NADPH oxidases (NOX) using apocynin (Apo) and diphenylene iodonium (DPI), or treatment with the antioxidant butylated hydroxyanisole (BHA), significantly reduced proliferation and induced apoptosis in HL cell lines. These effects correlated with transcriptomic alterations involving redox regulation, immune signaling, and cell cycle control. Interestingly, treatment with DPI or antioxidants attenuated constitutive Signal Transducer and Activator of Transcription (STAT) activity, as seen by decreased phospho-STAT6 levels and reduced STAT6 DNA binding. This suggests a sensitivity of the Janus kinase (JAK)/STAT pathway in cHL cell lines to O₂⁻ and H₂O₂ depletion. Functional assays confirmed this by demonstrating partial restoration of proliferation or apoptosis in L428 cells that expressed constitutively active STAT6 or were transfected with small interfering RNAs (siRNAs) that targeted STAT regulators. These findings highlight that oxidants, particularly H₂O₂, act as both general oxidative stressors and essential modulators of oncogenic signaling pathways. Specifically, maintenance of oxidant homeostasis is critical for sustaining JAK/STAT-mediated growth and survival programs in cHL cells. Targeting redox homeostasis might offer a promising therapeutic strategy to impair JAK/STAT-driven proliferation and survival in cHL. Full article

Cancer immunotherapy increasingly relies on nucleic acid-based vaccines, yet achieving efficient and safe delivery remains a critical limitation. Polyplexes—electrostatic complexes of cationic polymers and nucleic acids—have emerged as versatile carriers offering greater chemical tunability and multivalent targeting capacity compared to lipid nanoparticles, with lower immunogenicity than viral vectors. This review summarizes key design principles governing polyplex performance, including polymer chemistry, architecture, and assembly route—emphasizing microfluidic fabrication for improved size control and reproducibility. Mechanistically, effective systems support stepwise delivery: tumor targeting, cellular uptake, endosomal escape (via proton-sponge, membrane fusion, or photochemical disruption), and compartment-specific cargo release. We discuss therapeutic applications spanning plasmid DNA, siRNA, miRNA, mRNA, and CRISPR-based editing, highlighting preclinical data across multiple tumor types and early clinical evidence of on-target knockdown in human cancers. Particular attention is given to physiological barriers and engineering strategies—including size-switching systems, charge-reversal polymers, and tumor-penetrating peptides—that improve intratumoral distribution. However, significant challenges persist, including cationic toxicity, protein corona formation, manufacturing variability, and limited clinical responses to date. Current evidence supports polyplexes as a modular platform complementary to lipid nanoparticles in selected oncology indications, though realizing this potential requires continued optimization alongside rigorous translational development. Full article

Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk, particularly in aging populations. Postmenopausal osteoporosis (PMOP) remains the most common primary form and results from abrupt estrogen deficiency after menopause, which disrupts bone remodeling by accelerating the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis, suppressing Wnt/β-catenin signaling, and promoting inflammatory cytokine production. In contrast, drug-induced osteoporosis (DIOP) encompasses a heterogeneous group of secondary bone disorders arising from pharmacologic exposures. Glucocorticoids suppress osteoblastogenesis, enhance osteoclast activity, and increase reactive oxygen species; long-term bisphosphonate therapy may oversuppress bone turnover, resulting in microdamage accumulation; denosumab withdrawal triggers a unique rebound surge in RANKL activity, often leading to rapid bone loss and multiple vertebral fractures. Medications including aromatase inhibitors, SSRIs, proton pump inhibitors, heparin, and antiepileptic drugs impair bone quality through diverse mechanisms. Standard antiresorptive agents remain first-line therapies, while anabolic agents such as teriparatide, abaloparatide, and romosozumab provide enhanced benefits in high-risk or drug-suppressed bone states. Transitional bisphosphonate therapy is essential when discontinuing denosumab, and individualized treatment plans—including drug holidays, lifestyle interventions, and monitoring vulnerable patients—are critical for optimizing outcomes. Emerging approaches such as small interfering RNA (siRNA)-based therapeutics, anti-sclerostin agents, digital monitoring technologies, and regenerative strategies show promise for future precision medicine management. Understanding the distinct and overlapping molecular mechanisms of osteoporosis is essential for improving fracture prevention and long-term skeletal health. Full article

Atherosclerosis is a chronic, multifactorial vascular disease and the leading global cause of cardiovascular morbidity. Its development reflects interconnected disturbances in lipid metabolism, endothelial function, inflammation, smooth muscle cell (SMC) phenotypic switching, and extracellular matrix remodeling. Genetic predisposition, including monogenic disorders such as familial hypercholesterolemia and polygenic risk variants, modulates disease susceptibility by altering lipid homeostasis as well as inflammatory and thrombotic pathways. Epigenetic regulators and noncoding RNAs, such as histone modifications, microRNAs, and long noncoding RNAs, further shape gene expression and link environmental cues to vascular pathology. Endothelial injury promotes lipoprotein retention and oxidation, triggering monocyte recruitment and macrophage-driven foam cell formation, cytokine secretion, and necrotic core development. Persistent inflammation, macrophage heterogeneity, and SMC plasticity collectively drive plaque growth and destabilization. Emerging insights into immune cell metabolism, intracellular signaling networks, and novel regulatory RNAs are expanding therapeutic possibilities beyond lipid-lowering. Current and evolving treatments include statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, anti-inflammatory agents targeting interleukin-1 beta (IL-1β) or NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and advanced approaches such as gene editing, siRNA, and nanoparticle-based delivery. Integrating multi-omics, biomarker-guided therapy, and precision medicine promises improved risk stratification and next-generation targeted interventions. This review summarizes recent molecular advances and highlights translational opportunities for enhancing atherosclerosis prevention and treatment. Full article

Background: Lactate Dehydrogenase C (LDHC) is a promising therapeutic target due to its highly tumor-specific expression, immunogenicity, and oncogenic functions. We previously showed that LDHC silencing in triple-negative breast cancer (TNBC) cells enhances treatment response to DNA-damage response-related drugs, supporting its therapeutic potential. However, no selective LDHC inhibitors exist, highlighting the need for innovative targeting strategies. Methods: We assessed the physicochemical properties and evaluated the delivery efficiency, anti-tumor activity, and safety of four cell-penetrating peptides (CPPs)—R10, 10R-RGD, cRGD-10R, and iRGD-10R—for siRNA-mediated LDHC silencing in TNBC. Clonogenic assays were used to evaluate effects on olaparib sensitivity, and TNBC zebrafish xenografts were utilized to study in vivo anti-tumor activity. Results: All CPP:siRNA complexes formed uniform nanocomplexes (129–168 nm) with low polydispersity indices (<0.25) and positive zeta potentials (+6.47 to +29.6 mV). Complexes remained stable in human serum for 24 h and showed no significant cytotoxicity in TNBC and non-cancerous cell lines. The 10R-RGD and cRGD-10R:siLDHC complexes achieved 40% LDHC protein knockdown, reduced TNBC clonogenicity by 30–36%, and enhanced olaparib sensitivity. Treatment of TNBC zebrafish xenografts with 10R-RGD or cRGD-10R:siLDHC complexes significantly reduced tumor growth by approximately 50% without major toxicity. Conclusions: These results demonstrate that CPP-mediated siRNA delivery enables selective LDHC silencing with tumor growth inhibition in triple-negative breast cancer models. This approach represents a novel, effective, and safe proof-of-concept therapeutic strategy to target LDHC, with potential translational relevance as a standalone therapy or in combination with common anti-cancer drugs. Full article

Background: Keratoconus (KC) is a progressive corneal ectasia and a leading cause of corneal transplantation in young adults. Once regarded as a biomechanical disorder, KC is now recognized as a complex disease driven by genetic predisposition, epigenetic modulation, and environmental triggers. Advances in genomics and transcriptomics have begun to elucidate the molecular mechanisms underlying corneal thinning and ectasia. Objectives: This review synthesizes two decades of evidence on the genetic and epigenetic architecture of keratoconus, highlights key molecular pathways implicated by these findings, and discusses translational implications for early diagnosis, risk prediction, and novel therapeutic strategies. Methods: A narrative review was conducted of peer-reviewed human, animal, and in vitro studies published from 2000 to 2025, with emphasis on genome-wide association studies (GWAS), sequencing data, methylation profiling, and non-coding RNA analyses. Findings were integrated with functional studies linking genetic variation to molecular and biomechanical phenotypes. Results: Genetic studies consistently implicate loci such as ZNF469, COL5A1, LOX, HGF, FOXO1, and WNT10A, alongside rare variants in Mendelian syndromes (e.g., brittle cornea syndrome, Ehlers–Danlos spectrum). Epigenetic research demonstrates altered DNA methylation, dysregulated microRNAs (e.g., MIR184, miR-143, miR-182), and aberrant lncRNA networks influencing extracellular matrix remodeling, collagen cross-linking, oxidative stress, and inflammatory signaling. Gene–environment interactions, particularly with eye rubbing and atopy, further shape disease expression. Translational progress includes polygenic risk scores, tear-based biomarkers, and early preclinical studies using RNA-based approaches (including siRNA and antisense oligonucleotides targeting matrix-degrading and profibrotic pathways) and proof-of-concept gene-editing strategies demonstrated in corneal cell and ex vivo models. Conclusions: Keratoconus arises from the convergence of inherited genomic risk, epigenetic dysregulation, and environmental stressors. Integrating multi-omic insights into clinical practice holds promise for earlier detection, precision risk stratification, and development of targeted therapies that move beyond biomechanical stabilization to disease modification. Full article

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that causes progressive renal failure, nephrolithiasis, and nephrocalcinosis in children. It is characterized by hepatic overproduction of oxalate. Conventional management, which involves combined liver–kidney transplantation, vitamin B6 supplementation, and intense hydration, does not address the underlying metabolic defect for most patients and it generally provides only supportive care. The first approved disease-modifying treatment for pediatric PH1 is Lumasiran, a small interfering RNA (siRNA) therapeutic. By specifically inhibiting the hepatic glycolate oxidase mRNA, Lumasiran lowers the production of oxalate at its origin. Along with fewer kidney stone events and stabilization of nephrocalcinosis, clinical trials (ILLUMINATE-A/B/C) showed significant decreases in urinary oxalate excretion. The most frequently reported adverse event is mild injection-site reactions, which are generally well tolerated. The molecular mechanism, pharmacokinetics, and clinical effectiveness of Lumasiran in children with PH1 are compiled in this review. We go over possible long-term safety concerns, the impact of early intervention on renal outcomes, and the function of siRNA therapies in pediatric precision medicine. Furthermore, we highlight Lumasiran’s importance as a model for targeted treatment in uncommon pediatric kidney diseases by considering it in the larger context of RNAi-based therapies. A paradigm shift in pediatric nephrology is signaled by Lumasiran, which changes the therapeutic approach from supportive care to precision, targeted medicine. Further research and empirical data will clarify its long-term advantages, the best ways to treat it, and the possible use of siRNA technologies for other genetic renal disorders. Full article

Aortic valve stenosis (AVS) is the most common valvular disease in developed countries, and no pharmacological therapy is currently available. Increasing evidence identifies lipoprotein(a) [Lp(a)] as a causal factor linking lipid metabolism, inflammation, and valve calcification. Lp(a) levels are largely genetically determined and remain stable throughout life, making them a potential therapeutic target. This review summarizes the current evidence on Lp(a) and AVS pathophysiology, the diagnostic and prognostic role of Lp(a), and the therapeutic potential of Lp(a)-lowering agents. Emerging Lp(a)-targeted therapies, including antisense oligonucleotides and siRNA-based agents, could reshape AVS management by providing the first pharmacological option to slow disease progression in selected high-risk patients. Full article