Medroxyprogesterone acetate (MPA) is a major fertility-preserving therapeutic option for patients with endometrial cancer (EC); however, MPA resistance markedly restricts the efficacy of conservative treatments. Downregu...Medroxyprogesterone acetate (MPA) is a major fertility-preserving therapeutic option for patients with endometrial cancer (EC); however, MPA resistance markedly restricts the efficacy of conservative treatments. Downregulation of the progesterone receptor (PR) expression is a key determinant of MPA resistance; however, the underlying molecular mechanisms have not been elucidated comprehensively. In this study, we identified AMBRA1, a substrate-specific adaptor of CUL4-RING E3 ubiquitin ligase (CRL4), as a critical regulator of PR stability and the MPA response. AMBRA1 expression was significantly increased in MPA-resistant EC tissues, and its overexpression induced an MPA-resistant phenotype. Mechanistically, AMBRA1 promotes ubiquitin-mediated degradation of PR by targeting lysine 388 in a CRL4 complex-dependent manner. Moreover, pharmacological inhibition of the CRL4 complex with MLN4924, an FDA-approved antitumor drug that blocks NEDD8-dependent Cullin-RING ligase activation, stabilizes PR and markedly restores MPA sensitivity in MPA-resistant EC cell lines and patient-derived organoid models. Collectively, these findings suggest that the CRL4 ubiquitin ligase facilitates PR degradation, inducing resistance to MPA. Furthermore, this study identified the CRL4 complex as a potential therapeutic target for overcoming MPA resistance in EC.
Cardiovascular diseases (CVDs) remain a major cause of global morbidity and mortality, yet their complex pathophysiology is difficult to recapitulate in conventional mammalian models fully. Compared with traditional mamm...Cardiovascular diseases (CVDs) remain a major cause of global morbidity and mortality, yet their complex pathophysiology is difficult to recapitulate in conventional mammalian models fully. Compared with traditional mammalian and systems, zebrafish offer several distinct advantages for CVD research. Their small size, high fecundity, and rapid development make them particularly suitable for high-throughput screening, while embryonic transparency enables real-time, noninvasive imaging of dynamic cardiac processes. High genetic homology with humans, together with facile genetic manipulation, further supports their utility in modeling cardiovascular disorders. In addition, their unique capacity for cardiac regeneration provides a valuable platform for regeneration studies. A wide range of endogenous and exogenous zebrafish models have successfully recapitulated key features of human CVDs, thereby facilitating mechanistic investigation and the identification of critical signaling pathways. Zebrafish also enable cost-efficient phenotypic screening and have contributed substantially to early-stage drug discovery and cardiotoxicity assessment. In summary, despite anatomical differences from mammals, zebrafish combine genetic tractability, phenotypic fidelity, and screening efficiency, underscoring their value in advancing drug discovery and therapeutic development for CVDs.
Intervertebral disc (IVD) degeneration (IDD) involves nucleus pulposus (NP) cell death, but its mechanisms are unclear. PANoptosis is a novel cell death pattern whose role in IDD remains elusive. This study investigates...Intervertebral disc (IVD) degeneration (IDD) involves nucleus pulposus (NP) cell death, but its mechanisms are unclear. PANoptosis is a novel cell death pattern whose role in IDD remains elusive. This study investigates whether PANoptosis contributes to mechanical overloading-induced NP cell death and explores its underlying mechanisms. We evaluated PANoptosis in NP cells from human degenerated IVD tissues, aged mice, lumbar spine instability model, and an mechanical compression system. Results indicated that PANoptosis-related proteins were upregulated in NP cells from degenerated IVDs, as well as in those subjected to mechanical overloading both and . To confirm its functional role, we inhibited PANoptosis by interfering PANoptosis sensor Z-DNA-binding protein 1 (ZBP1). Results showed that ZBP1 inhibition partially reversed this upregulation, reduced NP cell death, and alleviated IDD. Mechanistically, we found Kindlin-2 loss promoted PANoptosis in NP cells by suppressing forkhead box P1 (FOXP1) SUMOylation and increasing ZBP1 promoter activity. Furthermore, mechanical overloading downregulated Kindlin-2 by impairing ciliary intraflagellar transport 88 (IFT88), thereby exacerbating PANoptosis and IDD. We show that ciliary IFT88 influences Kindlin-2, which protects NP cells from mechanical overloading-induced PANoptosis by enhancing FOXP1 SUMOylation. This pathway may offer a new therapeutic target for IDD.
The extent of the inflammatory response in the early stages of acute kidney injury (AKI) significantly influences renal damage, repair, and ultimately prognosis. Macrophages are key drivers of early inflammation in AKI,...The extent of the inflammatory response in the early stages of acute kidney injury (AKI) significantly influences renal damage, repair, and ultimately prognosis. Macrophages are key drivers of early inflammation in AKI, and their metabolic reprogramming is closely associated with their pro-inflammatory polarization. However, the mechanisms underlying this process remain incompletely understood. In this study, we combined single-cell RNA sequencing, metabolomics, and gene-editing approaches to, investigate how injured renal tubular epithelial cells regulate macrophage metabolism and phenotype in ischemia-reperfusion injury (IRI)-induced AKI. We found that injured proximal tubular cells secrete high levels of secreted phosphoprotein 1 (SPP1), which binds to CD44, a receptor abundantly expressed on infiltrating macrophages, thereby activating the downstream PI3K/AKT signaling pathway. This activation induces nuclear translocation of PKM2, a key metabolic enzyme, which drives glycolytic metabolic reprogramming in macrophages and promotes their polarization toward a pro-inflammatory phenotype. and functional experiments further confirmed that blocking the SPP1-CD44 axis, using siRNA, neutralizing antibodies, or conditional knockout strategies, effectively alleviates renal IRI in mice, reduces macrophage infiltration, and diminishes the inflammatory response. Overall, this study delineates a novel mechanism in which injured tubular cell-derived SPP1 communicates with macrophage CD44 to regulate immunometabolism and inflammatory polarization via the PI3K/AKT-PKM2 signaling module at the single-cell and metabolic levels. These findings provide both a potential therapeutic target and a mechanistic framework for the prevention and treatment of AKI.
Medulloblastoma is one of the most common malignant pediatric brain tumors. There remain significant challenges in investigating oncogenic mechanisms and evaluating therapeutic efficacy due to the limited available model...Medulloblastoma is one of the most common malignant pediatric brain tumors. There remain significant challenges in investigating oncogenic mechanisms and evaluating therapeutic efficacy due to the limited available models that accurately reflect tumor heterogeneity. To overcome this limitation, we established 10 patient-derived medulloblastoma organoids (MBOs) that retain the histological characteristics, and cellular diversity of the original tumors. These MBOs demonstrate strong infiltration capabilities, both through co-culture with human embryonic stem cell-derived cerebral organoids and following orthotopic or subcutaneous transplantation, establishing a potential platform for investigating interactions within the tumor microenvironment. Using integrated RNA sequencing, whole-exome sequencing, and DNA methylation profiling, we demonstrated that MBOs faithfully preserve the transcriptional, genomic, and epigenetic landscapes of their parental tumors. Single-cell transcriptomic analysis revealed conserved cellular subpopulation between MBOs and primary tumors. Our findings suggest that photoreceptor-related pathways may play an unprecedented role in the pathogenesis of Group 4 medulloblastoma and may be associated with interactions within the tumor microenvironment. Furthermore, we developed a prognostic nomogram based on IMPG2, BNC2, PAPPA2, ITGBL1and UNC13C expression levels in tumor cells to predict survival outcomes. Notably, tumor-infiltrating lymphocytes (TILs) expanded from patient specimens exhibited significant cytotoxic activity against autologous MBOs co-cultured and effectively suppressed the growth of subcutaneous MBO xenografts . These findings demonstrate the potential of TIL-based immunotherapy for medulloblastoma treatment. Collectively, our MBO system faithfully recapitulates critical tumor characteristics and serves as a valuable platform for investigating tumorigenic mechanisms and assessing therapeutic responses. This study not only promotes fundamental biological research but also accelerates clinical translation in medulloblastoma.
Osteoporosis (OP) is a chronic and severe skeletal metabolic disorder resulting from excessive bone erosion activity and compromised bone formation. Emerging evidence highlights that the "gut-bone" axis plays a critical...Osteoporosis (OP) is a chronic and severe skeletal metabolic disorder resulting from excessive bone erosion activity and compromised bone formation. Emerging evidence highlights that the "gut-bone" axis plays a critical role in maintaining bone homeostasis via modulating gut microbiota and relevant metabolites. Individually, diet-derived tryptophan acts as one of the primary environmental factors that modulate the microbiota-bone crosstalk. Nevertheless, the promising modulatory mechanism of the "diet-microbiome-bone" axis remains unknown during OP progression. In this regard, the study focused on the dominant role of tryptophan-restricted intermittent diet during estrogen deficiency-induced OP. Upon these findings, micro-computed tomography (μCT) evaluation and histomorphometric analysis have confirmed that treatment with tryptophan-restricted intermittent diet effectively mitigated bone loss and improved bone microarchitecture. To unravel the underlying mechanism, we performed 16S rDNA gene sequencing and untargeted metabolomics to confirm the alteration of microbial community composition and metabolite profiles. Additionally, biotin was further identified as a significant microbiota-derived metabolite involved in M1 macrophage polarization and mature osteoclast apoptosis when administered with tryptophan-restricted intermittent diet. Thus, we summarized that treatment with tryptophan-restricted intermittent diet could perform a protective function during OP via modulating the coupling effects of gut microbiota and bone homeostasis, which may provide a potential therapeutic strategy for OP.
Lung cancer has the highest mortality rate globally, yet the effective treatment options remain limited. Although short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate are known to modulate immune respon...Lung cancer has the highest mortality rate globally, yet the effective treatment options remain limited. Although short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate are known to modulate immune response and improve the efficacy of cancer therapy, the role of valerate in non-small cell lung cancer (NSCLC) remains unexplored. This study identifies valerate as a biased ligand for GABA receptor, which specifically binds the GABBR1 subunit, upregulates its expression, and thereby mediates CD8 T cell anti-tumor immunity in NSCLC. It is demonstrated that GABBR1 overexpression in lung cancer cells suppresses tumor growth both and . Single-cell RNA sequencing analysis of public datasets indicates that GABBR1 expression is associated with CXCL13. Mechanically, and experiments validate that valerate-induced upregulation of GABBR1 stimulates the secretion of CXCL13, which in turn promotes robust infiltration and activation of CD8 T cells within the tumor microenvironment. Furthermore, enrichment analysis pinpoints that CXCL13 secretion is negatively transcriptionally regulated by NRF2 and its co-factor ATF4. Analysis of patient samples further confirms that high GABBR1 expression correlates with a longer patient survival rate, underscoring its prognostic value. Overall, these findings identify valerate as a novel immunomodulatory metabolite and propose targeting GABBR1 as a promising strategy to potentiate cancer immunotherapy in lung cancer.
BACKGROUND: Paclitaxel-based intraperitoneal chemotherapy (IPC) is a cornerstone strategy for treating gastric cancer peritoneal metastasis (GCPM). However, a subset of patients exhibit resistance to this therapy. Our st...BACKGROUND: Paclitaxel-based intraperitoneal chemotherapy (IPC) is a cornerstone strategy for treating gastric cancer peritoneal metastasis (GCPM). However, a subset of patients exhibit resistance to this therapy. Our study revealed that glucose transporter type 3 (GLUT3) is a key mediator of paclitaxel resistance in GCPM, although its precise mechanism of action remains to be fully elucidated. METHODS: Single-cell (nucleus) sequencing and immunohistochemical staining were used to analyze paclitaxel-resistant and paclitaxel-sensitive GCPM tissue samples. GLUT3 was knocked down in AGS and HGC27 cells and overexpressed in MKN45 cells to establish the corresponding experimental models. The CUT&Tag and ChIP-qPCR techniques were utilized to elucidate the GLUT3-histone H3 lysine 18 lactylation (H3K18la)-mitogen-activated protein kinase associated protein 1 (MAPKAP1) regulatory axis. A mouse peritoneal metastasis model was used to evaluate the ability of GLUT3 targeting to reverse ferroptosis resistance and paclitaxel chemoresistance.Results: GLUT3, glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) expression was significantly upregulated in paclitaxel-resistant GCPM tissues. Elevated GLUT3 expression correlated with poor prognosis in GC patients. Functionally, GLUT3 knockdown sensitized GC cells to both Erastin and paclitaxel, whereas GLUT3 overexpression conferred therapeutic resistance. Mechanistically, GLUT3 upregulated hexokinase 3 (HK3) expression, increasing glucose-6-phosphate (G6P) and lactate production. Elevated lactate levels supported E1A binding protein p300 (p300)-mediated H3K18la enrichment at the MAPKAP1 promoter, thereby activating its transcription. Rescue assays indicated that depletion of MAPKAP1 restored ferroptosis sensitivity in GC cells. , compared with paclitaxel monotherapy, the combination of GLUT3 inhibition and paclitaxel not only reduced tumor weight by 75.47% () but also significantly suppressed the expression of MAPKAP1, GPX4, and SLC7A11. CONCLUSION: Targeting GLUT3-H3K18la-MAPKAP1 reverses paclitaxel resistance by inducing ferroptosis, providing a novel combination strategy for treating refractory GCPM.
Diabetic retinopathy (DR) arises from intertwined inflammatory, metabolic, and hypoxia-driven angiogenic programs, yet upstream regulators coordinating these processes remain incompletely defined. Here, we used an integr...Diabetic retinopathy (DR) arises from intertwined inflammatory, metabolic, and hypoxia-driven angiogenic programs, yet upstream regulators coordinating these processes remain incompletely defined. Here, we used an integrative multi-omics and experimental framework to identify cathepsin H (CTSH) as a candidate causal driver of proliferative DR (PDR). By combining GWAS, eQTL, pQTL, and mQTL datasets with Mendelian randomization, summary-data-based Mendelian randomization, and Bayesian colocalization, CTSH emerged as the strongest genetically supported candidate across discovery and validation analyses. In the UK Biobank (UKB), circulating CTSH was elevated in diabetic retinopathy and independently predicted incident disease. Single-cell transcriptomic analyses localized CTSH predominantly to myeloid compartments within fibrovascular membranes and linked CTSH-high states to inflammatory, hypoxic, and angiogenic programs. In high-glucose-stimulated THP-1 monocytes, CTSH promoted reactive oxygen species accumulation, NF-κB activation, and increased IL-6, TNF-α, HIF-1α, and VEGF expression, whereas CTSH silencing reversed these effects. Structure-guided virtual screening identified Eriocitrin as a lead CTSH-binding candidate. In db/db mice, intravitreal Eriocitrin improved inner-retinal function, restored OCTA-derived vascular metrics, and partially rescued retinal structure, with efficacy comparable to anti-VEGF treatment across several endpoints. Molecular analyses further showed coordinated suppression of inflammatory, hypoxic, angiogenic, and NF-κB signaling. Together, these findings identify CTSH as an upstream immunometabolic regulator of DR-related inflammatory and angiogenic biology, with the strongest genetic support observed for PDR, and support CTSH targeting as a potential multi-pathway therapeutic strategy beyond VEGF inhibition.
As the leading cause of global cancer-related mortality, lung cancer has a particularly poor prognosis among non-small cell lung cancer (NSCLC) subtypes, which constitute 85% of cases and are frequently diagnosed at adva...As the leading cause of global cancer-related mortality, lung cancer has a particularly poor prognosis among non-small cell lung cancer (NSCLC) subtypes, which constitute 85% of cases and are frequently diagnosed at advanced stages. Through integrated pharmacological approaches, this study elucidates the novel anti-NSCLC mechanism of patchouli alcohol (PA), a low-toxicity sesquiterpene alcohol. We confirmed that compared with conventional chemotherapeutics, PA induced autophagic cell death in NSCLC models (/) and resulted in superior biosafety profiles. Combining DARTS, molecular docking and CETSA, we subsequently identified GNAI1 as the direct molecular target of PA. ARRB1 was further characterized as the essential adaptor mediating PA/GNAI1-triggered autophagic cell death. Specifically, PA specifically disrupted the GNAI1-ARRB1 interaction, inhibiting downstream pro-survival pathways (ERK/JAK2-STAT3/mTOR) and ultimately leading to autophagic cell death in NSCLC cells. In summary, this work provides the first evidence that PA exerts anti-NSCLC effects by targeting the GNAI1/ARRB1 axis, offering a promising therapeutic strategy against advanced NSCLC.
Acute pancreatitis (AP) is a common emergency of the digestive system, with some cases progressing to severe acute pancreatitis (SAP), which threatens life. Intrapancreatic fat deposition (IPFD) denotes the abnormal infi...Acute pancreatitis (AP) is a common emergency of the digestive system, with some cases progressing to severe acute pancreatitis (SAP), which threatens life. Intrapancreatic fat deposition (IPFD) denotes the abnormal infiltration of lipid and pathological proliferation of adipocytes in pancreatic parenchyma. It has been demonstrated to bear a close correlation with the heightened risk and progressive development of acute pancreatitis, whereas the specific molecular and cellular mechanisms underlying this association remain poorly understood. This article elaborates on the mechanisms through which IPFD exacerbates acute pancreatitis from the following four perspectives: 1. IPFD causes pancreatic cell damage via lipotoxicity, such as inducing multiple forms of cell death in pancreatic acinar cells, damaging endothelial cells to trigger microcirculatory disorders, and interfering with ductal cells leading to pancreatic duct obstruction. 2. IPFD prematurely activates pancreatic enzymes by inducing adipocyte dysfunction, thereby forming a vicious cycle. 3. IPFD amplifies inflammatory responses by interfering with endocrine regulation. 4. IPFD mediates pancreatic fibrotic dysfunction to amplify AP-associated injury. In addition, this article conducts a thorough review and raises the urgent key issues that remain to be addressed in current research on the association between IPFD and the development of AP, providing new insights for future clinical applications in the future.
Cancer-associated fibroblasts (CAFs) contribute to the metastatic progression of high-grade serous ovarian cancer (HGSOC), partly through the transfer of regulatory RNAs via exosomes. Here, we identify a circRNA, circMPP...Cancer-associated fibroblasts (CAFs) contribute to the metastatic progression of high-grade serous ovarian cancer (HGSOC), partly through the transfer of regulatory RNAs via exosomes. Here, we identify a circRNA, circMPP6 as a key pro-metastatic factor enriched in CAF-derived exosomes. circMPP6 is upregulated in metastatic HGSOC tissues and is associated with poor prognosis. In HGSOC cells, nuclear circMPP6 interacts with SFPQ and NONO to stabilize ADAM22 mRNA, whereas cytoplasmic circMPP6 binds EEF1A2 to enhance ADAM22 protein expression. Elevated ADAM22 levels activate TGF-β/Smad2/3 signaling via binding to ITGB1, promoting proliferation, migration, and invasion and metastasis . Silencing circMPP6 or disrupting the ADAM22 axis attenuates these oncogenic phenotypes. In CAFs, its loading into exosomes is mediated by hnRNPA2B1, enabling its transfer to adjacent tumor cells. These findings reveal a dual regulatory mechanism by which CAFs-derived exosomal circMPP6 enhances ADAM22 expression and activates pro-metastatic TGF-β signaling in HGSOC. Our study highlights circMPP6 as a potential therapeutic target and critical mediator of stromal-tumor communication in ovarian cancer metastasis.
Obesity exacerbates rheumatoid arthritis (RA). However, the underlying mechanisms remain incompletely defined. Elucidating these mechanisms can help the identification of novel therapeutic targets. Herein, we used high-f...Obesity exacerbates rheumatoid arthritis (RA). However, the underlying mechanisms remain incompletely defined. Elucidating these mechanisms can help the identification of novel therapeutic targets. Herein, we used high-fat diet (HFD)-induced obese collagen-induced arthritis (CIA) mice to investigate these mechanisms. Immunohistochemistry revealed that obesity exacerbated joint inflammation and cartilage degradation. Next, integrated label-free quantitative proteomics and cytometry by time-of-flight (CyTOF) were used to characterize lymphocyte subsets. Proteomic profiling identified 26 differentially expressed proteins in obese versus lean CIA mice, including the transcription factors EOMES and KLF2, the TGFβ receptor (TGFβR) signaling component TGFBR2, and the tissue-resident memory (TRM) T cell marker CD103. CyTOF analysis revealed a robust 3.0-fold increase ( 0.0043) in the proportion of CD103⁺ TRM cells among CD3⁺ T cells in obese CIA mice, characterized by a large effect size. Immunofluorescence results confirmed this increase in synovial tissues. Treatment with asiaticoside (a TGF-β/Smad-suppressing triterpenoid) significantly reduced TRM cell proportions ( < 0.05) and ameliorated symptoms in obese CIA mice. Collectively, these findings establish a novel mechanistic axis in which obesity-induced TGFβR-hyperactivation promotes TRM cell accumulation, which exacerbates arthritis severity in this RA model. Our findings provide a preclinical rationale for targeting TGFβR/TRM in human RA with obesity as a comorbidity.
Intestinal ischemia/reperfusion (I/R) injury is a critical clinical syndrome precipitated by the restoration of blood flow following intestinal ischemia, a common occurrence in perioperative settings such as abdominal ao...Intestinal ischemia/reperfusion (I/R) injury is a critical clinical syndrome precipitated by the restoration of blood flow following intestinal ischemia, a common occurrence in perioperative settings such as abdominal aortic surgery, hemorrhagic shock, and cardiopulmonary bypass. This injury extends beyond the local gut, as the disruption of the intestinal mucosal barrier facilitates bacterial and endotoxin translocation into the systemic circulation, triggering a systemic inflammatory response that can progress to sepsis and multiple organ dysfunction syndrome (MODS). Despite advances in critical care, the mortality rate associated with severe intestinal I/R injury remains formidable. The microcirculatory disturbances and organ damage following intestinal I/R involve complex pathological processes, including metabolic injury and oxidative stress. In recent years, rapid developments in the understanding of cell death mechanisms, gut microbiota, microRNAs, and fundamental medical technologies have significantly advanced research on the prevention and treatment of I/R injury. This review aims to comprehensively summarize the occurrence and progression of intestinal I/R, its impact on extraintestinal organ injury, diagnostic strategies and biomarkers, as well as current treatment methods, thereby providing guidance for the future prediction, diagnosis, and treatment of intestinal I/R injury.
RNA 5-methylcytosine (mC) is an emerging epitranscriptomic modification implicated in the progression of multiple cancers, yet the landscape of mC in bladder cancer (BCa) and underlying regulatory mechanisms remains larg...RNA 5-methylcytosine (mC) is an emerging epitranscriptomic modification implicated in the progression of multiple cancers, yet the landscape of mC in bladder cancer (BCa) and underlying regulatory mechanisms remains largely elusive. In this study, we identified NOP2, an RNA methyltransferase, as a key driver of BCa progression. NOP2 was significantly upregulated in BCa tumors and associated with poor prognosis. Functionally, NOP2 promoted cell proliferation and invasion, enhancing tumor growth in xenograft models. Mechanistically, NOP2-mediated mC deposition facilitates the recruitment of the mC reader YBX1, thereby stabilizing mRNA and boosting SCD expression. The NOP2/SCD axis orchestrated lipid metabolism reprogramming, altering the distribution of saturated, monounsaturated, and polyunsaturated fatty acids to suppress lipid peroxidation and protect BCa cells from ferroptotic stress. Collectively, our findings determine the oncogenic role of the mC methyltransferase NOP2 in BCa and reveal a novel NOP2/YBX1/SCD axis that links epitranscriptomic regulation, metabolic reprogramming and ferroptosis evasion, providing a new target for therapeutic intervention.
Liver diseases pose a significant global health burden. This review systematically elucidates the crucial role of exercise as a non-pharmacological intervention in the prevention and treatment of various liver conditions...Liver diseases pose a significant global health burden. This review systematically elucidates the crucial role of exercise as a non-pharmacological intervention in the prevention and treatment of various liver conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), viral hepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Exercise effectively delays disease progression and improves patients' quality of life through multi-targeted mechanisms, such as improving glucose and lipid metabolism, enhancing insulin sensitivity, regulating immune-inflammatory responses, inhibiting hepatic stellate cell activation, and remodeling the tumor microenvironment. Future research should focus on developing individualized, precise exercise prescriptions and further exploring its molecular mechanisms by integrating multi-omics technologies, thereby providing innovative strategies for the comprehensive management of liver diseases.
Solid tumors create an acidic tumor microenvironment (TME) that drives cancer progression, therapy resistance, and immune evasion. Bicarbonate is crucial for maintaining acid-base balance, however, its role in non-small...Solid tumors create an acidic tumor microenvironment (TME) that drives cancer progression, therapy resistance, and immune evasion. Bicarbonate is crucial for maintaining acid-base balance, however, its role in non-small cell lung cancer (NSCLC) remains unclear. Through the analysis of single-cell RNA sequencing data and the TCGA and CPTAC databases, we identified solute carrier family 4 member 7 (SLC4A7) as the predominantly expressed bicarbonate transporter in NSCLC. Functionally, SLC4A7 knockdown impaired bicarbonate uptake, resulting in intracellular acidification and extracellular alkalinization. This phenomenon led to a decrease in glycolysis and subsequently suppressed the growth and metastasis of NSCLC. Both and data demonstrate that the alkalinization of the TME induced by Slc4a7 knockout enhances the infiltration and function of cytotoxic T cells, significantly inhibiting tumor growth. Additionally, Slc4a7 knockout exhibits synergistic antitumor efficacy in combination with PD-1/PD-L1 immune checkpoint inhibitors. Mechanistically, integrative analysis of RNA-seq and ATAC-seq data identified CTCF as a transcription factor regulating SLC4A7 expression. In summary, our study demonstrates that SLC4A7-mediated bicarbonate transport is crucial for maintaining acid-base homeostasis in NSCLC and represents a promising therapeutic target for this disease.
During metastasis, circulating tumor cells (CTCs) are subjected to fluidic shear stress (SS), which eliminates many of them but paradoxically enhances malignancy and metastatic success. Meanwhile, given the critical role...During metastasis, circulating tumor cells (CTCs) are subjected to fluidic shear stress (SS), which eliminates many of them but paradoxically enhances malignancy and metastatic success. Meanwhile, given the critical roles of reactive oxygen species (ROS) in stress response and cancer, we engineer a circulation-mimicking microfluidic system which generates pulsatile SS to investigate the interplay among SS, ROS and metastasis. A 3-hour SS treatment rapidly elevates ROS levels, boosting metastatic abilities in triple-negative breast cancer (TNBC) cells and . RNA-sequencing and subsequent investigation identify activator protein-1 (AP-1) transcription factor members FOS, ATF3 and FOSB, which undergo dramatic ROS-dependent increase and nuclear localization upon SS stimulation. All three genes exhibit metastasis-promoting potential, while FOS displays the strongest ability to trigger distant lung metastasis in an orthotopic tumor model and correlates with worse clinical outcomes. Mechanistically, calcium channel acts as the mechano-sensor to initiate the SS-ROS cascade, with calcium channel blockers Mibefradil and Nifedipine effectively weakening SS-ROS-induced invasiveness. Following ROS elevation, the downstream activation of p38-ELK1-cFOS and JNK-cJUN pathways subsequently increase the expression of malignancy-related genes. This metastasis-promoting SS-calcium channel-ROS-FOS axis provides new insights for combating metastatic progression in breast cancer.