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PubMed2026

Engineering extracellular vesicles for targeted siRNA delivery: Advances, therapeutic applications, and clinical translation.

Small interfering RNA (siRNA) therapeutics have emerged as a transformative approach for sequence-specific gene silencing, offering the potential to treat a broad spectrum of diseases by selectively suppressing disease-associated genes. However, the clinical translation of siRNA remains limited by rapid enzymatic degradation, poor cellular uptake, inadequate endosomal escape, and off-target effects, necessitating the development of efficient delivery systems. Extracellular vesicles (EVs) have gained considerable attention as natural nanocarriers owing to their excellent biocompatibility, low immunogenicity, intrinsic targeting capability, and ability to protect therapeutic cargo while traversing complex biological barriers. This review comprehensively discusses the biological characteristics of EVs, the molecular basis of RNA interference, and the major challenges associated with siRNA delivery [Fig. 1]. Recent advances in EV engineering, including cargo-loading strategies such as electroporation, sonication, extrusion, parent-cell engineering, and microfluidic approaches, together with surface functionalization using peptides, antibodies, aptamers, and hybrid nanoplatforms, are critically evaluated for improving targeting specificity and intracellular delivery. Furthermore, the therapeutic applications of engineered EV-mediated siRNA delivery in cancer, neurological disorders, liver diseases, cardiovascular diseases, inflammatory disorders, and infectious diseases are systematically summarized, highlighting their potential to enhance gene silencing while minimizing systemic toxicity. Current challenges related to large-scale manufacturing, cargo-loading efficiency, standardization, quality control, regulatory approval, and clinical translation are also discussed, together with emerging technologies involving synthetic biology, genome engineering, artificial intelligence, and multifunctional hybrid vesicles. Overall, engineered extracellular vesicles represent a highly versatile and biologically inspired platform for targeted siRNA delivery, providing a promising foundation for the development of next-generation precision RNA therapeutics and accelerating the clinical translation of gene-silencing strategies.

Extracellular vesicle engineering↗

PubMed2025

Substitutions of nucleotides at the 3' ends of COL6A1/2/3 exons induce exon skipping associated with collagen VI-related muscular dystrophies and therapeutic strategies.

PURPOSE: Collagen VI-related muscular dystrophies, characterized by proximal muscle weakness and joint contractures, are caused by pathogenic variants in the genes, COL6A1 to COL6A3. A monoallelic variant at the last nucleotide of a COL6A1 exon was initially classified as a missense variant but acted as a splicing variant, resulting in exon skipping. Here, we evaluated whether single-nucleotide variants at the 3'-ends of COL6A1 to COL6A3 exons cause aberrant splicing. METHODS: Ten relevant variants were identified in patients from our repository or public databases, and their muscle COL6A1 to COL6A3 transcripts were analyzed. The effects of the variants on splicing were also analyzed by minigene assay and SpliceAI in silico prediction. RESULTS: Transcripts from muscles of individuals with suspected collagen VI-related phenotypes showed exon skipping (skipping rate >12%). Findings of minigene assay and in silico prediction experiments supported these findings. Two therapeutic approaches, splicing correction of pre-messenger RNA or gene silencing of mature messenger RNA were assessed. Among them, gene silencing using short interfering RNAs targeting the skipped transcripts proved to be effective in restoring collagen VI in cells containing the pathogenic variant. CONCLUSION: Single-nucleotide variants at the 3'-ends of exons can lead to aberrant splicing, and allele-specific gene silencing targeting such variants is a promising therapeutic strategy.

Humans↗

PubMed2026

Chromatin-binding protein HMGN1 promotes HCC tumorigenesis via histone methylation-induced RALB transcriptional suppression.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with metastasis being the primary cause of its high mortality. The chromatin-binding protein, high mobility group nucleosome binding domain 1 (HMGN1), has been implicated in tumour progression, but its specific role and mechanism in HCC metastasis remain unclear. This study investigates the function of HMGN1 and its potential as a therapeutic target. Analysis of patient samples confirms an upregulation of HMGN1 in HCC tissues, correlating with advanced disease and poor prognosis. Functional assays demonstrate that HMGN1 promotes HCC metastasis in vitro and in vivo. Mechanistically, integrated RNA sequencing and chromatin immunoprecipitation sequencing analyses reveal that HMGN1 binds to the promoter of RAS-like proto-oncogene B (RALB) gene, recruiting the repressive histone mark H3K9me2 to epigenetically silence its transcription and drive metastasis. Therapeutically, a nanoparticle delivery system for siRNA against HMGN1 effectively silences its expression and inhibits metastasis in orthotopic liver xenograft tumour models. Our findings establish HMGN1 as a key epigenetic driver of HCC metastasis and highlight siRNA-nanoparticle targeting of HMGN1 as a promising precision therapeutic strategy.

Humans↗

PubMed2026

Emerging Nucleic Acid-Based Therapies for Hypercholesterolemia with Focus on a New Modality, Liver-Directed miR-30c Analog C2.

Despite major advances in lipid-lowering therapies, a significant unmet need remains, particularly for patients with homozygous familial hypercholesterolemia (HoFH), severe heterozygous familial hypercholesterolemia (HeFH), and those who fail to achieve guideline-recommended LDL-C targets. Nucleic acid-based therapeutics have emerged as a transformative approach for treating hypercholesterolemia. Antisense oligonucleotides and small interfering RNAs (siRNAs) have demonstrated durable hepatic gene silencing and have led to approved therapies, while gene replacement and in vivo genome-editing strategies offer the potential for long-lasting, and possibly one-time, interventions. In parallel, microRNAs (miRNAs) have attracted increasing interest because of their ability to coordinately regulate multiple genes involved in lipoprotein metabolism, cholesterol transport, and lipid homeostasis. Human genetic studies further support the importance of miRNA-mediated regulation, exemplified by a rare ~2.5 kb deletion in the distal LDLR 3'UTR ("del2.5") that disrupts miRNA-binding sites and is associated with lifelong low LDL-C levels. This review summarizes recent advances, mechanisms of action, clinical progress, and remaining challenges across antisense oligonucleotides, siRNAs, gene therapy, genome editing, and emerging miRNA-based therapeutics for hypercholesterolemia. As an example of the latter approach, the liver-directed miR-30c analog C2 has demonstrated preclinical activity by coordinately reducing hepatic lipoprotein secretion and lipogenesis while enhancing cholesterol elimination, resulting in reduced LDL-C and atherosclerosis. However, it must be noted that these findings remain preclinical, and further optimization of delivery, pharmacokinetics, safety, and long-term efficacy will be required before clinical evaluation. Continued advances in RNA chemistry, targeted delivery, and genome engineering are expected to further expand the therapeutic landscape for dyslipidemia and cardiovascular disease.

Humans↗

PubMed2025

Caffeic acid phenethyl ester protects renal tubular epithelial cells against ferroptosis in diabetic kidney disease via restoring PINK1-mediated mitophagy.

Mounting evidence indicates that renal tubular ferroptosis plays a crucial role in the progression of diabetic kidney disease (DKD). Caffeic acid phenethyl ester (CAPE), derived from propolis, a precious resinous substance synthesized by various bee species, has garnered broad attention in biomedical research. This study aims to explore the mechanism by which CAPE protects renal tubular epithelial cells (TECs) against ferroptosis in DKD. DBA/2J mice were administered streptozotocin (STZ) by intraperitoneal injection, fed a high-fat diet (HFD) and treated with CAPE. The findings revealed significant changes in ferroptosis markers. In diabetic mice and TECs under high-glucose (HG) conditions, levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) decreased, while transferrin receptor 1 (TFR1) increased. These changes were accompanied by a reduction in antioxidant capability and the accumulation of malondialdehyde (MDA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the intersection targets of CAPE and ferroptosis were mainly located in the mitochondria and exhibited high enrichment values in mitophagy. Further investigations revealed that HG induced a depolarization of mitochondrial membrane potential and an excessive level of mitochondrial reactive oxygen species (ROS), accompanied by defective mitophagy. The administration of CAPE inhibited exacerbated ferroptosis and rescued defective mitophagy induced by DKD. In addition, CAPE restored PTEN-induced putative kinase 1 (PINK1) levels, which were markedly diminished in the kidneys of DKD mice and TECs subjected to HG. Molecular docking simulation experiments suggested that CAPE is steadily bound to the PINK1 active pocket. Cellular Thermal Shift Assay (CETSA) and Drug Affinity Responsive Target Stability assay (DARTS) showed that CAPE enhances the thermal stability of the PINK1 protein within a specific temperature range and protects the PINK1 protein from degradation by proteolytic enzymes. These results confirm that CAPE interacts with PINK1 as its specific target. However, the positive outcomes of CAPE treatment on ferroptosis were nullified by the PINK1 siRNA. This research indicates that CAPE has potential therapeutic benefits for DKD by protecting renal TECs against ferroptosis via rescuing PINK1-mediated mitophagy. These findings suggest that CAPE shows potential as a therapeutic agent to prevent tubular injury in DKD.

Animals↗

PubMed2026

Using cancer profiles to identify synthetic lethal therapeutic targets and predictive biomarkers in cancer gene dependency data.

MOTIVATION: Large scale loss-of-function screens utilising CRISPR or siRNA can provide profound insights into the importance of individual genes for the survival of a cancer cell and can drive the identification of therapeutic targets and biomarkers, and the development of targeted drugs. However, the analysis of these data and the substantial bodies of metadata that relate to them, is technically challenging and typically requires substantial expertise in data science and computer coding. RESULTS: To facilitate the analysis of cancer gene dependency data by cancer biologists and clinical scientists, we have developed DepMine-a computational toolkit providing a powerful system for framing complex queries relating cancer gene dependency to the underlying genetic changes that occur in cancer cells. DepMine identifies synthetic lethal relationships between putative target genes and complex 'cancer profiles' built from user-specified combinations of mutations, copy-number variation, and expression levels, and can refine these to optimal biomarker definitions for target dependency. AVAILABILITY: The Python implementation of DepMine and associated data files can be obtained at https://github.com/UOSbioinformaticslab/depmine and is free to academics and Not-For-Profit organisations. The DepMine release referenced in this paper is archived as DOI: 10.5281/zenodo.19570601.

Humans↗

PubMed2026

LiCl induces GSK-3β mediated autophagy, DNA damage, and cell cycle arrest in HPV driven cervical cancer cells.

High-risk HPV infections induce cervical cancer progression by disrupting cellular homeostasis and survival pathways, including autophagy. Targeting autophagy represents a promising therapeutic strategy. Lithium chloride (LiCl), extensively studied for its neuroprotective properties, can be investigated for its potential anticancer effects in HPV-driven cervical cancer cells. Treatment with 30 mM LiCl induced significant phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, inducing functional inhibition and downstream signal alterations. This modulation of GSK-3β activity compromised genomic integrity, validated by increased double strand DNA breaks, increased oxidative and cellular stress, and reduced antioxidant enzyme activity. Consequently, LiCl treated cells exhibited significant G2/M phase arrest, indicating disruption in cell cycle progression. Interestingly, the observed cytotoxicity occurred independently of classical apoptotic pathways, suggesting the activation of alternative cell death mechanisms. Mechanistic studies revealed a robust autophagic flux, with GSK-3β mediated autophagy, validated through siRNA mediated knockdown experiments. These findings highlight a novel cytotoxic mechanism of LiCl and propose its potential repurposing from neurobiology to targeted cancer therapeutics.

Humans↗

PubMed2026

Target, silence, replace: a review on RNA-based drugs in modern medicine.

RNA therapies have evolved into a revolutionary approach in contemporary medicine for treating various diseases by directly targeting RNA molecules engaged in disease pathogenesis. These therapeutic agents regulate biological processes through diverse mechanisms, including modulation of RNA function and gene expression. Medical applications of RNA are greatly enhanced by its structure, adaptability, and capacity for targeted binding. Among these traits is its ability to bind to certain molecules unique to those chemicals. RNA-based treatments have emerged from advancements in the production, modification, and cellular transport of RNA molecules. Several RNA drugs have been approved whereas some are under trial for few diseases. RNA therapeutics can function at the level of RNAs, DNAs and proteins. The evolution of mRNA vaccines during the COVID-19 epidemic emphasizes the exciting potential of RNA therapies in the treatment of diseases. This article provides a comprehensive overview of the several forms of RNA therapies, including small-interfering RNA (siRNA), messenger RNA (mRNA), and antisense-oligonucleotides (ASOs), together with information on their action mechanisms and delivery strategies that improve cellular absorption and shield RNA molecules from degradation. Further, CRISPR-based editing of the genome can be employed for modification of target RNA sequences for various disorders. Development of RNA aptamers have also been identified as pivotal RNA-therapeutic candidate. Additionally, we have explained mechanistic details and examples of drugs approved for RNA therapy. Emphasizing their potential to enhance patient outcomes and fulfil unmet medical requirements, we also highlight the clinical development of RNA therapies in treating cancer and other infectious diseases.

RNA interference↗

PubMed2026

KLF5-driven G6PD protects lung squamous cell carcinoma from ferroptosis by sustaining mitochondrial homeostasis and SLC7A11-dependent cystine uptake.

AIMS: Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited therapeutic options. Ferroptosis has emerged as a promising antitumor strategy. However, the metabolic determinants governing ferroptotic vulnerability in LUSC remain incompletely understood. We investigated glucose-6-phosphate dehydrogenase (G6PD) in this context. MATERIALS AND METHODS: In vitro models using small interfering RNA (siRNA)-mediated G6PD depletion, together with pharmacological studies using 6-aminonicotinamide (6-AN) and LUSC xenograft models, were employed to investigate the underlying mechanisms. KEY FINDINGS: G6PD was markedly upregulated in LUSC, and analysis of the Cancer Genome Atlas lung squamous cell carcinoma (TCGA-LUSC) cohort showed that elevated G6PD expression was associated with advanced clinicopathological features and poorer overall survival. While ferroptosis inducers (erastin and RSL3) did not alter G6PD mRNA, they robustly increased G6PD protein during ferroptotic stress. Genetic or pharmacological inhibition of G6PD significantly sensitized LUSC cells to RSL3-induced ferroptosis, evidenced by enhanced lipid peroxidation, glutathione depletion, and ferrostatin-1-reversible cell death. Mechanistically, G6PD inhibition led to mitochondrial ferrous iron accumulation, elevated reactive oxygen species, impaired respiration, and activation of PINK1/Parkin-dependent mitophagy, which further exacerbated ferroptotic injury. In vivo, combined treatment with 6-aminonicotinamide and RSL3 markedly suppressed LUSC xenograft growth and enhanced biochemical markers of ferroptotic stress. Furthermore, G6PD protects cells by positively regulating the cystine/glutamate antiporter SLC7A11 to maintain redox homeostasis. Upstream, the oncogenic factor Krüppel-like factor 5 (KLF5) directly activates G6PD transcription. SIGNIFICANCE: Our findings identify a KLF5-G6PD-SLC7A11 axis as a critical metabolic safeguard against ferroptosis in LUSC. Targeting G6PD disrupts mitochondrial homeostasis, enhances mitophagy-dependent oxidative stress, and sensitizes tumors to ferroptotic therapy, highlighting a promising therapeutic strategy for LUSC.

Ferroptosis↗

PubMed2025

Novel insights into hypoxia-driven transcriptomic and epigenetic landscapes in grade 3 meningioma.

BACKGROUND: Meningiomas are among the most prevalent central nervous system (CNS) tumors, with up to 20% of cases exhibiting recurrence or aggressive behavior. Hypoxia is a key driver of malignant transformation and therapeutic resistance, yet its molecular basis in meningioma remains poorly understood. METHODS: We conducted integrative transcriptomic and epigenomic profiling of IOMM-Lee cells (grade 3 meningioma) cultured under hypoxic (0.2% O₂) and normoxic conditions. RNA-sequencing and Illumina MethylationEPIC v2.0 data were analyzed in R using DESeq2 and minfi, respectively. Functional enrichment, transcription-factor binding analysis, and pathway mapping (clusterProfiler, enrichR) were performed. Findings were cross-validated in public meningioma datasets, in Indian meningioma patient cohort and cell line via RT-qPCR, and azacytidine-based demethylation assay. Functional role of the candidate gene was elucidated in vitro via cellular assays. RESULTS: Hypoxia triggered a canonical HIF1A-driven transcriptional program activating glycolytic and angiogenic pathways while downregulating genes associated with DNA repair and replication in meningioma. Several differentially expressed genes (DEGs) were identified as known oncogenes, tumor-suppressors, or associated with immune regulation and stemness. Promoter motif analysis identified HIF1, SP1, TP53, BRCA1, and E2F1 as enriched transcriptional regulators. We validated hypoxia and HIF1-mediated regulation of some of the top DEGs. DNA-methylation analysis revealed epigenetic silencing of RTN4IP1 and ZBTB7C under hypoxia, reversible upon azacytidine treatment. Integrative comparison with patient datasets highlighted SLITRK2, PDE4C, SGCD, and LRP1B as hypoxia-responsive genes associated with poor prognosis. Several hypoxia-regulated genes also showed significant correlation with known hypoxia biomarkers, VEGFA and CA9. IGFBP3 and NDRG1 were among the top hypoxia-associated upregulated genes, and IGFBP3 expression was linked to advanced meningioma grades. Knockdown of IGFBP3 via siRNA in hypoxia-treated IOMM-Lee cells was associated with reduced cell proliferation and migration. CONCLUSIONS: This study presents the first integrated transcriptomic–epigenomic landscape of hypoxia in grade 3 meningioma, uncovering regulatory networks and candidate biomarkers with prognostic and therapeutic potential. These findings provide a foundation for future translational studies targeting hypoxia-driven tumor progression in meningioma.

Humans↗

PubMed2026

Desmoplakin loss in alveolar epithelium drives Wnt/β-Catenin-mediated extracellular matrix remodeling and fibrotic signaling in vitro.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease characterized by aberrant extracellular matrix (ECM) remodeling, epithelial dysfunction, and limited therapeutic options. Genetic studies implicate Desmoplakin (DSP), a desmosomal adhesion protein, in IPF susceptibility; however, its mechanistic role remains unclear. This study aimed to investigate the role of DSP in regulating fibrotic and ECM remodeling pathways in alveolar epithelial cells. METHODS AND RESULTS: DSP was silenced using siRNA in adenocarcinoma-derived human alveolar epithelial A549 cells. DSP loss induced epithelial-to-mesenchymal transition, enhanced cell migration, and increased epithelial permeability, along with upregulation of fibrotic and ECM-associated genes. Pathway enrichment analysis of DSP interactors (STRING database) identified the Wnt/β-catenin signaling as a potential key pathway. Mechanistic validation using cycloheximide chase assays, qPCR, western blotting, immunofluorescence, and luciferase-reporter assays suggested that DSP loss destabilizes desmosomal complexes, promoting plakoglobin (γ-catenin) degradation while reducing β-catenin turnover. This was associated with increased nuclear accumulation of β-catenin and enhanced TCF/LEF-dependent transcription, leading to elevated expression of ECM-related genes, including COL1A1 and MMP9. DSP overexpression suppressed Wnt/β-catenin signaling and fibrotic gene expression, while pharmacological inhibition of this pathway attenuated DSP-dependent increases in ECM-associated gene expression. CONCLUSION: These findings suggest that DSP may function as a regulator of alveolar epithelial homeostasis and extracellular matrix remodeling in an in vitro epithelial model. Loss of DSP is associated with activation of Wnt/β-catenin-mediated fibrotic signaling, correlating with reduced plakoglobin stability. This study provides mechanistic insight into epithelial-matrix crosstalk in vitro and identifies a candidate pathway that may contribute to ECM dysregulation in IPF, the disease relevance of which will require validation in primary human alveolar epithelial cells and in vivo models.

Humans↗

PubMed2026

Genome-scale CRISPR screening uncovers SRSF6 as a target to sensitize hepatocellular carcinoma to radiotherapy.

BACKGROUND & AIMS: Radiotherapy confers clinical benefits to patients with hepatocellular carcinoma (HCC) across all stages, yet its clinical efficacy is limited by radioresistance. This study aimed to identify key regulators of HCC radiosensitivity through genome-wide functional screening. METHODS: A genome-wide CRISPR-Cas9 screen in Huh7 cells identified radiosensitivity regulators, with SRSF6 validated by siRNA knockdown and γ-H2AX assessment. Stable shRNA-mediated SRSF6 knockdown was established in Huh7 and HepG2 cells, followed by clonogenic, EdU incorporation, apoptosis, micronucleus, and comet assays. Mechanistically, RNA-seq, Western blotting, mRNA stability assays, RIP-qPCR, and RAD51 overexpression rescue assays were performed. The therapeutic potential of the SRSF6 inhibitor indacaterol was evaluated using MTS assays, HCC xenograft mouse models (BALB/c-nu/nu, n = 28), and HCC patient-derived organoids (PDOs) (n = 3). In addition, SRSF6 expression and its correlation with patient survival were analyzed using data from The Cancer Genome Atlas and a tissue microarray (n = 14 HCC and 14 paired adjacent non-tumorous liver samples). RESULTS: We identified the RNA-binding protein SRSF6 as a driver of HCC radioresistance. SRSF6 depletion enhanced the radiosensitivity of HCC cells (p <0.05-0.0001) by post-transcriptionally destabilizing the mRNAs of critical DNA repair genes (p <0.05-0.0001), thereby impairing radiation-induced DNA damage repair. The radiosensitizing effect of SRSF6 depletion was partially abrogated by ectopic overexpression of the core DNA repair protein RAD51 (p <0.05-0.001). Indacaterol exhibited cytotoxic effects on HCC cells (p <0.05-0.0001) and enhanced the antitumor efficacy of radiation in vivo (p <0.05-0.0001), as further validated across multiple HCC patient-derived organoids (p <0.05-0.0001). CONCLUSIONS: SRSF6 is a key regulator of HCC radioresistance through its post-transcriptional control of DNA repair capacity, and represents a novel therapeutic target to sensitize HCC to radiotherapy. IMPACT AND IMPLICATIONS: In this study, we performed a genome-wide CRISPR-Cas9 knockout library screen to dissect the molecular determinants governing HCC radiosensitivity, and identified RNA-binding protein SRSF6 as a driver of HCC radioresistance. We demonstrate that SRSF6 depletion disrupts the post-transcriptional stability of key DNA repair gene mRNAs and enhances HCC radiosensitivity. These findings are important for radiation oncologists and translational researchers, as they identify SRSF6-dependent RNA regulation as a critical determinant of radiotherapy response in HCC. Practically, we show that the clinically approved bronchodilator indacaterol suppresses SRSF6 function and enhances the antitumor efficacy of radiotherapy, offering a readily repurposable pharmacological strategy to overcome radioresistance. These implications are based on preclinical evidence across multiple models; however, future clinical trials are needed to validate the safety and efficacy of indacaterol-based radiosensitization in patients with HCC.

DNA repair↗

PubMed2026

PPRC1 is a prognostic biomarker and key regulator of mitochondrial oxidative phosphorylation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.

Humans↗

PubMed2026

Furmonertinib inhibits non-small cell lung cancer progression through ANGPT1-mediated regulation of cell migration and apoptosis.

BACKGROUND: Lung cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for effective therapeutic agents. This study investigates the antitumor effects and underlying mechanisms of furmonertinib (FUR) in lung cancer cells. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to identify FUR target genes, followed by functional enrichment, survival, and protein-protein interaction (PPI) network analyses. Human lung cancer cell line A549 was treated with FUR and/or ANGPT1-specific siRNA. Cell migration, apoptosis, and protein expression were assessed by wound healing, flow cytometry, and Western blotting. Cellular thermal shift assay (CETSA) and drug affinity response target stability (DARTS) assays were used to assess FUR-induced stabilization of angiopoietin-1 (ANGPT1) protein. RESULTS: FUR treatment significantly inhibited cell migration and increased apoptosis in NSCLC cells. Bioinformatics analysis revealed 12 overlapping target genes of FUR from the PharmMapper and SwissTargetPrediction databases, with ANGPT1 emerging as a key candidate. ANGPT1 expression was downregulated in tumor tissues and positively correlated with patient survival. Western blotting confirmed that FUR upregulated ANGPT1 protein levels in a dose-dependent manner. Knockdown of ANGPT1 enhanced migration and suppressed apoptosis, while FUR reversed these effects. FUR treatment enhanced the stability of ANGPT1 under high-temperature conditions while reducing its sensitivity to protease. ANGPT1 may have affected tumor cell migration through cell adhesion and extracellular matrix (ECM) pathways. CONCLUSIONS: FUR suppresses lung cancer progression by upregulating ANGPT1, thereby inhibiting cell migration and promoting apoptosis. ANGPT1 is a potential therapeutic target and provides new insights into the anti-tumor mechanism of FUR in lung cancer.

Lung cancer↗

PubMed2026

Targeted Epigenetic Silencing of Jumonji Domain-Containing Protein 3 Alleviates Nuclear Factor-Kappa B-Mediated Inflammation in Familial Mediterranean Fever.

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory condition caused by variants in the MEFV gene encoding pyrin, the essential component of the NLRP3/NF-κB complex of inflammasomes. Deregulation of nuclear factor-kappa B (NF-κB), a key proinflammatory mediator, leads to chronic inflammation in autoinflammatory/autoimmune diseases. Epigenetic modulation offers a new approach to regulate inflammasome activity, with Jumonji domain-containing protein 3 (JMJD3) being a promising target for managing inflammatory illnesses. GSK-J4 is a selective inhibitor of JMJD3, restricting pro-inflammatory cytokines and inflammation. AIM: Our research aimed to elucidate the role of JMJD3 and the NF-κB-JMJD3 signaling pathways in regulating inflammation in an in vitro model, and to investigate GSK-J4's effect in inhibiting inflammasome activation in primed peripheral blood mononuclear cells (PBMCs) isolated from FMF cases. METHODS: PBMCs were cultured and primed with LPS, and then treated with GSK-J4. JMJD3 knockdown was achieved using siRNA interference. Cellular inflammatory dynamics were assessed by Western blotting (WB) and ELISA. The qRT-PCR was used for gene expression quantification. Untreated cells served as a negative control. RESULTS: Our results showed significantly downregulated gene expression of NF-κB, NLRP3, and inflammatory cytokines in GSK-J4-treated cells compared to untreated cells, as confirmed by ELISA. WB reported a reduction of NF-κB in induced cells following GSK-J4 treatment. Knocking down JMJD3 also showed decreased levels of JMJD3, NF-κB, and inflammatory cytokines, indicating its proinflammatory role. CONCLUSION: The study showed that selective inhibition or silencing of JMJD3 significantly suppressed the inflammasome in FMF cases, suggesting its role as a therapeutic target for alleviating inflammation in various autoinflammatory diseases.

Humans↗

PubMed2026

UBE2D4 Upregulation Promotes Cuproptosis Sensitivity in Colorectal Cancer.

BACKGROUND: Cuproptosis, a copper-dependent form of regulated cell death, represents a potential therapeutic vulnerability in colorectal cancer (CRC). However, the regulatory mechanisms governing cuproptosis in CRC remain largely unknown. METHODS: UBE2D4 expression was analyzed in the TCGA-COAD cohort and validated in CRC cell lines (HCT116, HT29) and normal colon epithelial cells (FHC) by qRT-PCR and western blot. Paired CRC and adjacent normal tissues (n = 5) were also examined by western blot. UBE2D4-knockdown HT29 cells were generated by transient siRNA transfection to assess cell viability (CCK-8), migration (wound healing assay), and expression of cuproptosis-related genes (DLAT, HSP70, LIAS) under copper overload conditions (elesclomol+CuSO4). RESULTS: UBE2D4 was significantly upregulated in CRC tissues and cell lines compared to normal controls. In paired clinical samples, western blot confirmed that UBE2D4 protein expression was elevated in tumor tissues, accompanied by increased DLAT, HSP70 and LIAS. Copper overload induced typical cuproptotic mitochondrial morphology and triggered a marked upregulation of UBE2D4, DLAT, and HSP70, alongside downregulation of LIAS. UBE2D4 silencing had no effect on baseline cell viability or migration but significantly rescued cells from copper-induced cytotoxicity. Genetically, UBE2D4 knockdown specifically attenuated the copper-induced elevation of DLAT, while restoring HSP70 and LIAS to near-baseline levels. CONCLUSION: These findings identify UBE2D4 as a genetically upregulated and functionally significant gene in colorectal cancer. Its upregulation correlates with altered expression of cuproptosis-related genes, particularly DLAT, suggesting that UBE2D4 expression status may represent a genetic determinant of cuproptosis sensitivity in CRC. This study provides a genetic basis for stratifying CRC patients who might benefit from copper-based therapeutic strategies.

Humans↗

PubMed2026

Histone demethylase PHF2 drives olanzapine-induced dyslipidemia via epigenomic rewiring of hepatic lipogenic genes.

Olanzapine, an atypical antipsychotic agent, is widely used in treating psychotic disorders, yet its metabolic side effects remain a clinical concern. Emerging evidence suggests that dynamic alterations in histone methylation are implicated in olanzapine-induced hepatic lipid metabolic disorders. PHF2, a JmjC family histone demethylase mediating H3K9me2 demethylation, functions as a transcriptional repressor by regulating downstream targets. To elucidate PHF2's role in this process, we utilized an olanzapine-induced dyslipidemia rat model. ChIP-qPCR analysis demonstrated a significant reduction in dimethylated histone H3 lysine 9 (H3K9me2) on the promoters of lipogenic genes (Fasn, Acc1, Scd1) in the liver, accompanied by elevated nuclear expression of PHF2 in olanzapine-treated rats. Co-immunoprecipitation (Co-IP) assays revealed a physical interaction between PHF2 and ChREBP, a glucose-responsive lipogenic transcription factor. Olanzapine was found to enhance the formation of this complex. Overexpression of PHF2 led to upregulated protein levels of FASN/ACC1 and intracellular lipid accumulation, whereas knockdown of PHF2 using siRNA attenuated these effects. Notably, the upregulation of FASN/ACC1 expression induced by olanzapine was markedly diminished in PHF2-deficient AML12 cells via ChREBP-PHF2-mediated H3K9me2 demethylation. Additionally, olanzapine inhibited the nuclear translocation of FOXA2, a PHF2 transcriptional regulator, thereby augmenting PHF2 expression. These findings uncover a novel epigenetic mechanism underlying olanzapine-induced dyslipidemia, positioning the FOXA2-PHF2-ChREBP axis as a potential therapeutic target through modulation of hepatic histone methylation.

Animals↗

PubMed2024

Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models.

Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.

Animals↗