Metastasis remains a major therapeutic challenge in hepatocellular carcinoma (HCC), yet its underlying molecular mechanisms are not fully understood. This study reveals that ZCCHC4 acts as a key promoter of HCC metastasi...Metastasis remains a major therapeutic challenge in hepatocellular carcinoma (HCC), yet its underlying molecular mechanisms are not fully understood. This study reveals that ZCCHC4 acts as a key promoter of HCC metastasis. We demonstrate that ZCCHC4 enhances the metastatic capacity of HCC cells both and . Mechanistically, ZCCHC4 upregulates key lipid biosynthesis enzymes (HMGCR, SQLE, FASN, and SCD), leading to intracellular accumulation of cholesterol and fatty acids which drive metastasis. Concurrently, ZCCHC4 transcriptionally activates TMEM97, thereby augmenting Wnt signaling. Furthermore, TMEM97 interacts with LCN2 to retain it in the cytoplasm. This sequestration relieves LCN2-mediated inhibition of the transcription factor Twist1, consequently promoting epithelial-mesenchymal transition (EMT) and metastasis. Consistent with these findings, ZCCHC4 level positively correlates with levels of TMEM97 and the lipid enzymes in clinical HCC specimens, and high ZCCHC4 expression is associated with poor patient prognosis. In summary, our work identifies ZCCHC4 as a critical metastasis driver via coordinated regulation of lipid metabolism and the TMEM97/LCN2/Twist1 axis, presenting novel potential targets for treating HCC metastasis.
Recent evidence establishes the brain metastatic microenvironment as a key regulator of metastatic outgrowth, with oligodendrocytes being established as essential components of the brain metastatic microenvironment. None...Recent evidence establishes the brain metastatic microenvironment as a key regulator of metastatic outgrowth, with oligodendrocytes being established as essential components of the brain metastatic microenvironment. Nonetheless, the mechanisms underlying oligodendrocyte-mediated brain metastasis in lung cancer await clarification. Using orthogonal experimental models spanning clinical specimens and animal models, we investigated the presence and functional roles of oligodendrocytes in lung cancer brain metastasis (LCBM). Combinatorial approaches including scRNA-seq, functional genomics, and mechanistic studies revealed ERBB3 as the critical paracrine factor mediating oligodendrocyte-tumor crosstalk. Through comprehensive analysis, we demonstrated the infiltration of oligodendrocytes in the metastatic niche of LCBM. Functional assays demonstrated that oligodendrocytes significantly enhanced the proliferation, migration, and invasion of brain metastatic cells of lung cancer. Mechanistically, oligodendrocyte-secreted ERBB3 acts as a copper chaperone that competitively mobilizes extracellular copper ions through high-affinity binding to SLC31A1 on tumor cells, thereby promoting intracellular copper accumulation. Additionally, elevated ERBB3 expression in LCBM clinical specimens correlated with significantly reduced overall survival and targeted ERBB3 suppressed lung cancer brain metastasis. Our findings establish oligodendrocyte-derived ERBB3 as a critical mediator of intercellular copper transfer via SLC31A1 binding, which coordinately drives brain metastasis progression. Therapeutic targeting of this copper signaling axis represents a promising strategy against LCBM.
BACKGROUND AND AIMS: The liver has a unique capacity for self-renewal, maintaining a proper liver-to-bodyweight ratio, which is essential for sustaining homeostasis. Regenerative process in the liver involves intricate c...BACKGROUND AND AIMS: The liver has a unique capacity for self-renewal, maintaining a proper liver-to-bodyweight ratio, which is essential for sustaining homeostasis. Regenerative process in the liver involves intricate communication between various cell types such as hepatocytes, hepatic stellate cells, endothelial cells, and inflammatory cells. Although the role of endothelial cells in liver regeneration has been extensively studied, detailed knowledge regarding specific endothelial cell-derived factors that promote the regeneration of liver endothelial cells (LECs) remains limited. This study aimed to identify the regenerative capacity of endothelial progenitor cells (EPCs) after acute liver injury. METHODS: Thioacetamide (TAA) was used to induce acute liver injury. Bulk and single-cell RNA sequencing were analyzed to investigate changes in endothelial cells after TAA injection. heterozygous mice were analyzed to investigate the role of RUNX2 in endothelial regeneration. RESULTS: TAA resulted in the delamination of LECs, which exhibited the highest regenerative capacity after three days of TAA injection. TAA increased the number of EPCs and RUNX2 was significantly enriched in the EPC population. Endothelial RUNX2 promotes regeneration by regulating its target genes such as , , , , and . In addition, haplodeficient mice exhibited diminished liver regenerative capacity compared with wild-type mice. RUNX2 is also expressed in the endothelial cells of patients with chronic liver diseases. CONCLUSION: These findings provide novel insights into the intricate mechanisms regulating LEC regeneration and highlight the pivotal role played by RUNX2 in vascular remodeling.
Non-small-cell lung cancer (NSCLC) is the predominant form of lung cancer and the leading cause of cancer-related mortality worldwide, largely due to its aggressive progression and resistance to current therapies. B7-H3...Non-small-cell lung cancer (NSCLC) is the predominant form of lung cancer and the leading cause of cancer-related mortality worldwide, largely due to its aggressive progression and resistance to current therapies. B7-H3 has emerged as a novel immunotherapeutic target worthy of investigation. Luteolin, a flavonoid polyphenolic compound abundantly present in vegetables and herbs, has demonstrated significant anti-tumor effects in various cancer types. However, its therapeutic mechanism of action in NSCLC remains poorly understood. This study aimed to examine the combined effects of luteolin and B7-H3-targeted immunotherapy in NSCLC. The results demonstrated that luteolin suppressed NSCLC cell proliferation in a dose-dependent manner and exhibited enhanced combined effects with B7-H3 inhibition, while also promoting apoptosis. This combination strategy produced significant inhibitory effects both and . A B7-H3-targeted bispecific killer cell engager (BiKE) was constructed, and antibody-dependent cell-mediated cytotoxicity (ADCC) was measured to evaluate its combined effect with luteolin. The B7-H3-targeted BiKE showed superior activity when combined with luteolin compared to either treatment of luteolin or BiKE alone. Our findings not only identify B7-H3 as a promising therapeutic target for NSCLC but also suggest luteolin as a potential anticancer adjuvant. The rationally designed combination strategy presented here may enhance existing treatment paradigms for NSCLC.
Pseudouridine (Ψ) modification is a prevalent epitranscriptomic mark with critical roles in carcinogenesis; however, the function of its catalytic "writer" enzyme, pseudouridine synthase 1 (PUS1), in renal cell carcinoma...Pseudouridine (Ψ) modification is a prevalent epitranscriptomic mark with critical roles in carcinogenesis; however, the function of its catalytic "writer" enzyme, pseudouridine synthase 1 (PUS1), in renal cell carcinoma (RCC) remains elusive. Our analysis revealed that mRNA is upregulated in RCC and is associated with an unfavorable prognosis. Strikingly, this transcriptional upregulation results in a concomitant and exclusive increase in the protein abundance of PUS1 isoform 2. Mechanistically, although PUS1 markedly enhances global mRNA translation, this effect is not directly mediated via Ψ modification of either mRNA or tRNA. Instead, PUS1 regulates pre-mRNA splicing, and its deficiency induces elevated intron retention. This, in turn, culminates in the formation of double-stranded RNA (dsRNA), which subsequently activates the innate antiviral immune response and inhibits global translation. Furthermore, depletion of PUS1 in tumor cells significantly sensitizes RCC to immune checkpoint blockade therapy. Collectively, our findings demonstrate that PUS1 shields tumor cells from endogenous dsRNA accumulation and the consequent detrimental innate immune activation, thereby unveiling a novel and promising therapeutic strategy for RCC.
Dysregulated lipid metabolism and chronic inflammation are hallmarks of aging, yet their interplay in age-related tissue disorders remains poorly defined. In the ocular surface, age-related meibomian gland dysfunction (A...Dysregulated lipid metabolism and chronic inflammation are hallmarks of aging, yet their interplay in age-related tissue disorders remains poorly defined. In the ocular surface, age-related meibomian gland dysfunction (ARMGD) is highly prevalent but mechanistically unclear, leading to significant visual impairment without targeted therapies. To identify key molecular drivers of ARMGD, we performed integrated multi-omics screening of aging mouse meibomian glands (MGs) and identified DHCR24, a key cholesterol metabolism enzyme, as a critical regulator of gland homeostasis. Single-cell sequencing identified age-associated downregulation of predominantly in meibocytes. Based on this finding, we generated a meibocyte-specific knockout (cKO) model, which exhibited typical ARMGD pathology including glandular atrophy, disrupted lipid homeostasis, and inflammatory activation. Further studies using SZ95 sebocytes demonstrated that DHCR24 deficiency induces mitochondrial dysfunction and cytosolic mitochondrial DNA (mtDNA) leakage, triggering cGAS/STING-dependent inflammatory senescence. Notably, AAV-mediated restoration of DHCR24 in mice reversed age-related gland pathology. Our findings establish DHCR24 as a dual-target regulator that maintains cholesterol metabolic homeostasis while suppressing mtDNA-driven inflammation via the cGAS-STING pathway, highlighting its therapeutic potential for ARMGD and related disorders characterized by lipid-inflammatory imbalance.
Uncoupling proteins (UCPs) are transmembrane proteins located in the inner membrane of mitochondria. They can reduce the efficiency of ATP synthesis and promote heat production by mediating the uncoupling oxidative phosp...Uncoupling proteins (UCPs) are transmembrane proteins located in the inner membrane of mitochondria. They can reduce the efficiency of ATP synthesis and promote heat production by mediating the uncoupling oxidative phosphorylation process. Different subtypes of UCPs have distinct tissue distributions and functional characteristics, involving various biological processes including temperature regulation, energy balance, signal transduction, oxidative stress, and the inflammatory response. In recent years, many studies have shown the potential value of UCPs in the prevention and treatment of metabolic diseases such as obesity, diabetes, cardiovascular diseases, neurological diseases, and tumors. Importantly, multiple evidence reveals that innovative therapies targeting uncoupling proteins will show broad application prospects in the future. This review of recent research on UCPs aims to provide a direction for exploring the molecular mechanisms of cellular homeostasis and intervention strategies for metabolic diseases.
Clear cell renal cell carcinoma (ccRCC), the most common and lethal subtype of renal cell carcinoma, exhibits marked intratumoral heterogeneity and complicates clinical management. Although long noncoding RNAs (lncRNAs)...Clear cell renal cell carcinoma (ccRCC), the most common and lethal subtype of renal cell carcinoma, exhibits marked intratumoral heterogeneity and complicates clinical management. Although long noncoding RNAs (lncRNAs) regulate diverse cellular processes, their landscape and biomarker potential in ccRCC remain poorly defined. Here we performed single-nucleus and bulk transcriptomic, proteomic, and metabolomic analyses on a cohort of 100 ccRCC patients. The expression pattern of lncRNAs were described based on metacells. Malignant cells displayed broader but lower lncRNA expression, likely reflecting copy number alterations, whereas low-abundance lncRNAs in normal epithelial cells showed individual variability. Multi-omics integration was used to establish a preliminary lncRNA functional inference pipeline, identifying lncRNAs involved in metabolic and immune processes and validating their roles through functional and experiments. Candidate biomarkers lncRNAs were identified to build diagnostic (DMRlnc) and prognostic models (PMRlnc), which were validated in TCGA, CheckMate, and IMmotion151 cohorts. DMRlnc achieved high diagnostic accuracy in both discovery and TCGA-KIRC cohorts (AUC 0.98 and 0.93). PMRlnc stratified patients into distinct risk groups with significant differences (p < 0.0001) across TCGA-KIRC and IMmotion151 cohorts. PMRlnc further indicated that low-risk patients may benefit more from nivolumab, while high-risk patients might respond better to atezolizumab plus bevacizumab.
BACKGROUND: Liver fibrosis is characterized by excessive extracellular matrix deposition and hepatic stellate cell (HSC) activation, driven by chronic liver injury and inflammation. Macrophages play dual roles in fibroge...BACKGROUND: Liver fibrosis is characterized by excessive extracellular matrix deposition and hepatic stellate cell (HSC) activation, driven by chronic liver injury and inflammation. Macrophages play dual roles in fibrogenesis; the dynamic balance between pro-fibrotic and anti-fibrotic subsets is critical in determining the progression or regression of the disease. NEDD4L, an E3 ubiquitin ligase, is well-known to be involved in cell biological processes by promoting protein degradation, yet its role in macrophages and liver fibrosis remains poorly understood. METHODS: Myeloid cell-specific knockout ( Lyz-Cre+, ) were generated, and subjected to carbon tetrachloride (CCl) and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced experimental liver fibrosis models. RESULTS: Single-cell RNA sequencing and transcriptomic analyses revealed significant upregulation of in macrophages from human and murine fibrotic livers. Strikingly, myeloid cell-specific deficiency exacerbated liver fibrosis in both mouse models, as evidenced by increased collagen deposition and elevated expression of fibrogenic genes in mice. Notably, mice with deficient in macrophages had more pro-fibrotic scar-associated macrophage (SAM) infiltration compared with mice in two experimental models. More interestingly, coculture experiments further verified that TGF-β1-treated deficient macrophages promoted HSC activation due to greater activation of SMAD3 signaling. Mechanistically, NEDD4L directly ubiquitinated phosphorylated SMAD3 and led to its degradation, thus limiting TGF-β1/SMAD3 signaling in macrophages. Moreover, hepatic levels of NEDD4L were significantly elevated in patients with liver fibrosis, positively correlating with hepatic levels of several fibrogenic genes. CONCLUSIONS: NEDD4L serves as a critical negative regulator of liver fibrosis by restraining profibrotic SAM expansion through ubiquitination and degradation of p-SMAD3 in macrophages. These findings highlight that targeting the ubiquitin-proteasome system as a potential therapeutic strategy for the treatment of fibrotic disease.
Postoperative cognitive dysfunction (POCD) in the elderly is a serious clinical concern. Although microglial phagocytosis is known to depend on mitochondrial metabolism, and its dysregulation can lead to abnormal synapti...Postoperative cognitive dysfunction (POCD) in the elderly is a serious clinical concern. Although microglial phagocytosis is known to depend on mitochondrial metabolism, and its dysregulation can lead to abnormal synaptic pruning and neuronal injury, the molecular link between these processes in POCD pathogenesis requires further elucidation. In this study, we established a POCD animal model of aged mice using isoflurane exposure and partial hepatectomy to investigate how anesthesia and surgery impacted synaptic plasticity via microglial phagocytosis. Our findings demonstrated that anesthesia and surgery significantly reduced hippocampal peroxisome proliferators-activated receptor γ coactivator-1α (PGC-1α) expression, leading to impaired mitochondrial energy metabolism, abnormal microglial phagocytosis and excessive synaptic pruning, which was associated with synaptic deficits and cognitive dysfunction. Importantly, the treatment with the PGC-1α activator ZLN005 or AAV-mediated overexpression of PGC-1α not only successfully restored PGC-1α level in the hippocampus of aged mice, but also effectively ameliorated mitochondrial dysfunction, reversed abnormal microglia-mediated synaptic pruning, restored synaptic plasticity, and improved POCD. Our findings identify microglial PGC-1α as a critical mediator in the pathogenesis of POCD, linking mitochondrial energy metabolism with microglia-mediated synaptic pruning, and highlight the potential of microglial PGC-1α as a promising therapeutic target for prevention and treatment of POCD.
Laryngeal squamous cell carcinoma (LSCC) is typically diagnosed at advanced stages, highlighting the critical need for early intervention. By integrating single-cell and bulk RNA-seq data from LSCC, vocal cord leukoplaki...Laryngeal squamous cell carcinoma (LSCC) is typically diagnosed at advanced stages, highlighting the critical need for early intervention. By integrating single-cell and bulk RNA-seq data from LSCC, vocal cord leukoplakia (VCL), and LSCC precursors, we characterized dynamic remodeling of the tumor microenvironment during LSCC pathogenesis. We identified transcriptional program gene modules that reflect malignant epithelial cells (maEpCs). The infiltration of POSTN fibroblasts progressively increases from normal tissue to VCL and further to LSCC, accompanied by enhanced intercellular communication. These fibroblasts interact with maEpCs and endothelial cells via ligands such as MIF, promoting epithelial-mesenchymal transition, cancer stemness, and angiogenesis. Blocking MIF reversed cancer-associated fibroblast-driven invasion and angiogenesis. Here, we further revealed that an immunosuppressive microenvironment arises as early as the precancerous stage, with VCL exhibiting CD8 T cell exhaustion and abundant LAMP3 dendritic cells that correlate positively with Tregs and exhausted CD8 T cells, promoting early immune escape. Additionally, LSCC was uniquely enriched for a pro-tumor SPP1 macrophage subset with low phagocytic activity and high angiogenic potential, linked to poor prognosis. Our findings uncover key mechanisms driving LSCC malignant progression, offer insights for early diagnosis and prognosis assessment, and highlight MIF as a promising therapeutic target.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, in which the role of lipophagy, a selective autophagic process degrading lipid droplets (LDs), remains poorly characterized. This...Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, in which the role of lipophagy, a selective autophagic process degrading lipid droplets (LDs), remains poorly characterized. This study investigated lipophagy and its key regulator, , in PDAC progression. Through immunofluorescence analysis of patient samples, transgenic mouse tissues, and cell lines, we find that lipophagy is elevated in PDAC and correlates with poor prognosis. Single-cell transcriptomic analysis identified as a critical lipophagy regulator and an independent clinicopathological indicator. Functional assays, including orthotopic and subcutaneous xenografts, demonstrated that promotes tumor growth. Mechanistically, OSBPL10 functionally cooperates with VAPA/VAPB to facilitate rapid lysosomal repair via ATG2A, thereby promoting lipophagy and lipid mobilization. Inhibition of lysosomal function abrogated the pro-lipophagic and pro-tumorigenic effects of OSBPL10. Collectively, our findings demonstrate that upregulated drives PDAC progression by enhancing lipophagy through ATG2A-mediated rapid lysosomal repair, highlighting OSBPL10 as a potential therapeutic target in PDAC.
Yang P, Xie Y, Lei Y
… +17 more, Huang X, Wu J, Zhang J, Peng S, Chen Y, Wei X, Zhang J, Yang Q, Li J, Dai W, Wu X, Shi X, Hu Y, Liu S, Li A, Tang W, Wang J
Pseudogene-derived long non-coding RNAs (lncRNAs) contribute to carcinogenesis. However, the role of the pseudogene ANXA2P1 in gastric cancer (GC) growth and glucose metabolism remains unknown. Analysis of microarray and...Pseudogene-derived long non-coding RNAs (lncRNAs) contribute to carcinogenesis. However, the role of the pseudogene ANXA2P1 in gastric cancer (GC) growth and glucose metabolism remains unknown. Analysis of microarray and RNA sequencing (RNA-seq) reveals that ANXA2P1 is increased upon glucose starvation in GC cells and displays elevated expression in GC. Moreover, ANXA2P1 overexpression promotes proliferation and metastasis by enhancing aerobic glycolysis in GC. Mechanistically, ANXA2P1 binds to the RNA-binding protein hnRNP F and promotes proximal polyadenylation site usage of HK2, thereby generating a short 3'UTR isoform with enhanced stability. Consequently, elevated HK2 expression accelerates GC proliferation and metabolic reprogramming. Interestingly, HK2 exerts a non-metabolic role by serving as a co-activator of transcription factor c-Myc to collaboratively drive ANXA2P1 expression. Clinically, ANXA2P1, hnRNP F, HK2, and c-Myc were augmented in specimens from GC patients compared to matched normal gastric mucosa. This study illustrates that ANXA2P1 is considered an oncogene, and the ANXA2P1-hnRNP F-HK2/c-Myc positive feedback loop may act as a potential therapeutic target for GC.
Docetaxel (DTX) is a standard chemotherapy agent for castration-resistant prostate cancer (CRPC); however, DTX resistance remains a major clinical challenge, and the underlying molecular mechanisms are not fully understo...Docetaxel (DTX) is a standard chemotherapy agent for castration-resistant prostate cancer (CRPC); however, DTX resistance remains a major clinical challenge, and the underlying molecular mechanisms are not fully understood. In our study, it was found that OTUB2 was highly expressed in DTX-resistant CRPC and could be served as a key driver of DTX resistance. Mechanistically, OTUB2 stabilizes the m5C reader ALYREF by removing its K48-linked polyubiquitin chains, leading to increased ALYREF protein levels. And then, ALYREF enhances the mRNA stability and expression of ABCG4, thereby promoting ATP-dependent efflux of DTX. Moreover, the expression of OTUB2 mRNA and protein could be regulated by FOXD3-AS1 derived from cancer-associated fibroblasts (CAFs). More importantly, treatment with OTUB2 inhibitor (OTUB2-IN-1) resensitized resistant CRPC to DTX. Together, our findings establish OTUB2 as a novel driver of DTX resistance in CRPC and highlight the role of CAFs-derived FOXD3-AS1 and OTUB2/ALYREF/ABCG4 axis in modulating DTX resistance of CRPC.
Gargalionis AN, Papavassiliou KA, Giannopoulou AI
… +12 more, Sarantis P, Piperi C, Lakiotaki E, Stofas A, Adamopoulos C, Kontou P, Boviatsis E, Korfias S, Kavantzas N, Korkolopoulou P, Basdra EK, Papavassiliou AG
Mechanotransduction critically shapes tumor progression by regulating cytoskeletal remodeling, epithelial-to-mesenchymal transition (EMT), invasion, and immune evasion. Polycystin-1 (PC1) and polycystin-2 (PC2), establis...Mechanotransduction critically shapes tumor progression by regulating cytoskeletal remodeling, epithelial-to-mesenchymal transition (EMT), invasion, and immune evasion. Polycystin-1 (PC1) and polycystin-2 (PC2), established mechanosensitive proteins in epithelial systems, have recently been implicated in tumor biology; however, their roles across diverse solid malignancies remain insufficiently defined. We assessed PC1 and PC2 expression patterns and their associations with clinicopathological features in human lung, breast, prostate, and brain tumors. PC1 functional modulation was performed in xenograft models using an extracellular mechanosensitivity-blocking antibody, and in cancer cell lines via () siRNA. We evaluated consequences on EMT, tumor growth, migration, and the mechanotransduction effector TAZ. PC1 and PC2 exhibited strong positive correlation across multiple tumor types, indicating coordinated mechanobiological regulation in cancer. Their expression associated with clinically aggressive features, including PD-L1 expression in lung cancer, adverse pathological characteristics in prostate cancer, and poorer survival in HER2⁺ breast cancer with elevated PC2 levels. , inhibition of PC1 mechanosensing consistently attenuated EMT programs across tumor types, accompanied by reductions in tumor growth. , silencing reduced cell migration and induced context-dependent modulation of EMT markers. Notably, PC1 suppression induced TAZ activation in breast cancer and glioma cells, indicating a cell type-specific regulatory interaction between PC1 and Hippo-mechanotransduction signaling. Our data suggest that polycystins, PC1 in particular, exert conserved yet context-dependent mechanoregulatory functions in solid tumors. By influencing EMT, migration, tumor progression, and TAZ-mediated mechanotransduction, PC1 emerges as a potential biomarker and mechanotherapeutic target in mechanically responsive cancers.
Amino acid metabolism is central to the liver's multifaceted physiology, serving as the cornerstone for protein homeostasis, metabolic integration, and tissue repair and regeneration. In addition, the dysregulation of am...Amino acid metabolism is central to the liver's multifaceted physiology, serving as the cornerstone for protein homeostasis, metabolic integration, and tissue repair and regeneration. In addition, the dysregulation of amino acid metabolism is intricately linked to the pathogenesis and progression of a wide spectrum of liver diseases, acting as a central pathological driver beyond a passive metabolic consequence. In metabolic dysfunction-associated steatotic liver disease (MASLD), characteristic alterations in circulating branched-chain amino acids (BCAAs) and glycine levels directly promote hepatic steatosis, oxidative stress, and inflammation. The progression to hepatocellular carcinoma (HCC) is fueled by a profound metabolic reprogramming that creates a dependency on amino acids like glutamine and aspartate for energy and biomass, while methionine and tryptophan metabolism foster an immunosuppressive microenvironment and epigenetic dysregulation to facilitate immune evasion and tumor growth. Furthermore, in liver fibrosis and cirrhosis, metabolic adaptations support disease progression, whereas in hepatic encephalopathy, the hallmark imbalance between BCAAs and aromatic amino acids, coupled with ammonia neurotoxicity, disrupts neurotransmitter balance. These disease-specific alterations not only provide robust biomarkers for diagnosis and prognosis but, more importantly, reveal critical therapeutic vulnerabilities. Consequently, targeting amino acid metabolism emerges as a promising strategic avenue, encompassing dietary interventions, targeted supplementation, and pharmacological inhibition for the development of novel therapeutics across the landscape of liver diseases. This review aims to systematically expound on these dual physiological and pathological roles, arguing that such disease-specific metabolic alterations not only provide biomarkers but, more importantly, unveil targetable vulnerabilities, thereby positioning amino acid metabolism as a strategic frontier for developing novel therapeutics across liver diseases.
Ovarian cancer represents a leading cause of mortality among gynecologic cancers, with limited therapeutic options for advanced and recurrent disease, highlighting an urgent need for innovative immunotherapies. Natural K...Ovarian cancer represents a leading cause of mortality among gynecologic cancers, with limited therapeutic options for advanced and recurrent disease, highlighting an urgent need for innovative immunotherapies. Natural Killer (NK) cells, functioning as crucial effector cells of the innate immune system, have been identified as promising candidates for ovarian cancer treatment. This review systematically examines the evolving landscape of NK cell-based therapies for ovarian cancer, spanning their preclinical rationale, clinical translation, and innovative combination strategies. Nevertheless, the highly immunosuppressive tumor microenvironment (TME) of ovarian cancer and barriers to tumor infiltration pose significant challenges to their clinical efficacy. Here, we discuss various therapeutic strategies (such as cytokine-based agents, NK cell engagers and chimeric antigen receptor NK cells) designed to enhance NK cell activity, which leverage the unique characteristics of NK cells to complement standard treatments and potentiate combination immunotherapies. Ongoing preclinical and clinical investigations are paramount to converting these advances into efficacious therapies, ultimately revolutionizing the therapeutic paradigm for ovarian cancer.
Chemoradiotherapy is the principal approach for treating a wide range of human cancers. However, its therapeutic outcomes in clinical settings are frequently impaired by resistance to tumor chemoradiotherapy. In this stu...Chemoradiotherapy is the principal approach for treating a wide range of human cancers. However, its therapeutic outcomes in clinical settings are frequently impaired by resistance to tumor chemoradiotherapy. In this study, we demonstrated that kinesin family member 26A (KIF26A) is downregulated in chemoradioresistant colorectal cancers, as revealed by transcriptomic analyses of colorectal cancer tissues and cell lines. Reduced KIF26A levels predicted diminished responsiveness to chemoradiotherapy and unfavorable outcomes in patients with colorectal cancer. Furthermore, lower KIF26A expression was associated with colorectal cancer (CRC) progression, migration, and invasion. This is the first demonstration that KIF26A interacts with Ku70 to suppress the formation of the DNA-dependent protein kinase (DNA-PK) complex, thereby preventing activation of non-homologous end joining (NHEJ) for repairing DNA damage. This makes cancer cells more vulnerable to DNA damage from chemoradiotherapy, thereby enhancing their sensitivity. To address chemoradio-resistance in KIF26A-low-expressing cells, we ascertained that histone deacetylase inhibitors (HDACi) could enhance acetylation of the KIF26A promoter, upregulate KIF26A, and boost the sensitivity of chemoradiotherapy-resistant cells. Thus, our research elucidates the function of KIF26A in the NHEJ repair process and indicates that combining HDACi with chemoradiotherapy may serve as a promising therapeutic modality for colorectal cancer.
FRMD5, FERM-domain protein 5, has been reported to be associated with tumors progession and neurodevelopment, however its molecular mechanisms in normal cells and its functions during urinary epithelium development remai...FRMD5, FERM-domain protein 5, has been reported to be associated with tumors progession and neurodevelopment, however its molecular mechanisms in normal cells and its functions during urinary epithelium development remain unknown. In this study, we identified that Frmd5 interacts with Jak2 and Stat3, leading to the enhanced Jak2/Stat3 complex formation and subsquently promoting phosphorylation of Stat3. In a urinary epithelium specific knockout of mouse, Jak2-Stat3 signaling pathway was significantly inactivated and apoptosis of epithelium was significantly downregulated compared with ; control mouse. In ; vaginal epithelium pro-apoptotic genes (, ) was decreased and anti-apoptotic genes (, ) was increased compared with ; vaginal epithelium. A total of 56.7% ; mice failed to form vaginal lumen and developed longitudinal vaginal septum coupled with infertility in these mice. In summary, we demonstrated that Frmd5 is essential for activation of Jak2-Stat3 signaling pathway and is required for vaginal lumen development in mice.