Identification of m6A/m5C-related lncRNA signature for prediction of prognosis and immunotherapy efficacy in esophageal squamous cell carcinoma.

N6-methyladenosine (m6A) and 5-methylcytosine (m5C) RNA modifications have garnered significant attention in the field of epigenetic research due to their close association with human cancers. This study we focus on elucidating the expression patterns of m6A/m5C-related long non-coding RNAs (lncRNAs) in esophageal squamous cell carcinoma (ESCC) and assessing their prognostic significance and therapeutic potential. Transcriptomic profiles of ESCC were derived from public resources. m6A/m5C-related lncRNAs were obtained from TCGA using Spearman's correlations analysis. The m6A/m5C-lncRNAs prognostic signature was selected to construct a RiskScore model for survival prediction, and their correlation with the immune microenvironment and immunotherapy response was analyzed. A total of 606 m6A/m5C-lncRNAs were screened, and ESCC cases in the TCGA cohort were stratified into three clusters, which showed significantly distinct in various clinical features and immune landscapes. A RiskScore model comprising ten m6A/m5C-lncRNAs prognostic signature were constructed and displayed good independent prediction ability in validation datasets. Patients in the low-RiskScore group had a better prognosis, a higher abundance of immune cells (CD4 + T cell, CD4 + naive T cell, class-switched memory B cell, and Treg), and enhanced expression of most immune checkpoint genes. Importantly, patients with low-RiskScore were more cline benefit from immune checkpoint inhibitor treatment (P < 0.05). Our findings underscore the potential of RiskScore system comprising ten m6A/m5C-related lncRNAs as effective biomarkers for predicting survival outcomes, characterizing the immune landscape, and assessing response to immunotherapy in ESCC.

Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes.

Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future.

Research progress and treatment of radiation enteritis and gut microbiota.

Radiation enteritis is a kind of intestinal radiation injury in patients with pelvic and retroperitoneal malignancies after radiotherapy, and its occurrence and development process are very complicated. At present, studies have confirmed that intestinal microecological imbalance is an important factor in the formation of this disease. Abdominal radiation causes changes in the composition of the flora and a decrease in its diversity, which is mainly manifested by a decrease in beneficial bacterial species such as Lactobacilli and Bifidobacteria. Intestinal dysbacteriosis aggravates radiation enteritis, weakens the function of the intestinal epithelial barrier, and promotes the expression of inflammatory factors, thereby aggravating the occurrence of enteritis. Given the role of the microbiome in radiation enteritis, we suggest that the gut microbiota may be a potential biomarker for the disease. Treatment methods such as probiotics, antibiotics, and fecal microbiota transplantation are ways to correct the microbiota and may be an effective way to prevent and treat radiation enteritis. Based on a review of the relevant literature, this paper reviews the mechanism and treatment of intestinal microbes in radiation enteritis.

Endoplasmic reticulum stress in diabetic kidney disease: adaptation and apoptosis after three UPR pathways.

Diabetes kidney disease (DKD) is one of the common chronic microvascular complications of diabetes, which has become the most important cause of modern chronic kidney disease beyond chronic glomerulonephritis. The endoplasmic reticulum is one of the largest organelles, and endoplasmic reticulum stress (ERS) is the basic mechanism of metabolic disorder in all organs and tissues. Under the stimulation of stress-induced factors, the endoplasmic reticulum, as a trophic receptor, regulates adaptive and apoptotic ERS through molecular chaperones and three unfolded protein reaction (UPR) pathways, thereby regulating diabetic renal damage. Therefore, three pathway factors have different expressions in different sections of renal tissues. This study deeply discussed the specific reagents, animals, cells, and clinical models related to ERS in DKD, and reviewed ERS-related three pathways on DKD with glomerular filtration membrane, renal tubular reabsorption, and other pathological lesions of different renal tissues, as well as the molecular biological mechanisms related to the balance of adaption and apoptosis by searching and sorting out MeSH subject words from PubMed database.

Endoplasmic Reticulum Stress Could Predict the Prognosis of Cervical Cancer and Regulate the Occurrence of Radiation Mucositis.

The endoplasmic reticulum (ER) is an important cellular organelle, and ER dysfunction has an important impact on a variety of biological processes. In this study, we explored the role of ER stress in cervical cancer by establishing a prognostic model related to ER stress. This study included 309 samples from the TCGA database and 15 pairs of RNA sequencing data before and after radiotherapy. ER stress characteristics were obtained by the LASSO regression model. The prognostic value of risk characteristics was analyzed by Cox regression, Kaplan‒Meier, and ROC curves. The effects of radiation and radiation mucositis on ER stress were evaluated. We found that ER stress-related genes were differentially expressed in cervical cancer and could predict its prognosis. The LASSO regression model suggested that risk genes had a strong ability to predict prognosis. In addition, the regression suggests that the low-risk group may benefit from immunotherapy. Cox regression analysis showed that FOXRED2 and N staging could be independent factors affecting prognosis. ERN1 was significantly affected by radiation and may be related to the occurrence of radiation mucositis. In conclusion, ER stress activation might have a high value in the treatment and prognosis of cervical cancer and has good clinical prospects.

Neutral amino acid transporter SLC38A2 protects renal medulla from hyperosmolarity-induced ferroptosis.

Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by Slc38a2-gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that Slc38a2-knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that Slc38a2 is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.

Aquaporins in Skin.

The skin is the largest organ of our body and plays a protective role against the external environment. The skin functions as a mechanical and water permeability barrier, assisting with thermoregulation and defending our body against a variety of stresses such as ultraviolet radiation, microbial infection, physical injuries, and chemical hazards. The structure of the skin consists of three main layers: the hypodermis, the dermis, and the epidermis. Aquaporins (AQPs) are a family of integral membrane proteins whose function is to regulate intracellular fluid hemostasis by facilitating the transportation of water, and in some cases small molecules, across the cell membranes. Up to six different AQPs (AQP1, 3, 5, 7, 9, and 10) are expressed in a variety of cell types in the skin. The AQP family plays an important role in these various locations, contributing to many key functions of the skin including hydration, wound healing, and immune responses. The involvement of different aquaporin family members in skin is discussed.

Targeting the DP2 receptor alleviates muscle atrophy and diet-induced obesity in mice through oxidative myofiber transition.

BACKGROUND: Mammalian skeletal muscles consist of two main fibre types: slow-twitch (type I, oxidative) and fast-twitch (type IIa, fast oxidative; type IIb/IIx, fast glycolytic). Muscle fibre composition switch is closely associated with chronic diseases such as muscle atrophy, obesity, type II diabetes and athletic performance. Prostaglandin D2 (PGD2 ) is a bioactive lipid derived from arachidonic acid that aggravates muscle damage and wasting during muscle atrophy. This study aimed to investigate the precise mechanisms underlying PGD2 -mediated muscle homeostasis and myogenesis. METHODS: Skeletal muscle-specific PGD2 receptor DP2-deficient mice (DP2fl/fl HSACre ) and their littermate controls (DP2fl/fl ) were subjected to exhaustive exercise and fed a high-fat diet (HFD). X-linked muscular dystrophy (MDX) mice and HFD-challenged mice were treated with the selective DP2 inhibitor CAY10471. Exercise tolerance, body weight, glycometabolism and skeletal muscle fibre composition were measured to determine the role of the skeletal muscle PGD2 /DP2 signalling axis in obesity and muscle disorders. Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the PGD2 /DP2-mediated skeletal muscle fibre transition. RESULTS: PGD2 generation and DP2 expression were significantly upregulated in the hindlimb muscles of HFD-fed mice (P < 0.05 or P < 0.01 vs. normal chow diet). Compared with DP2fl/fl mice, DP2fl/fl HSACre mice exhibited remarkable glycolytic-to-oxidative fibre-type transition in hindlimb muscles and were fatigue resistant during endurance exercise (154.9 ± 6.0 vs. 124.2 ± 8.1 min, P < 0.05). DP2fl/fl HSACre mice fed an HFD showed less weight gain (P < 0.05) and hepatic lipid accumulation (P < 0.01), reduced insulin resistance and enhanced energy expenditure (P < 0.05) compared with DP2fl/fl mice. Mechanistically, DP2 deletion promoted the nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) by suppressing RhoA/Rho-associated kinase 2 (ROCK2) signalling, which led to enhanced oxidative fibre-specific gene transcription in muscle cells. Treatment with CAY10471 enhanced NFATc1 activity in the skeletal muscles and ameliorated HFD-induced obesity (P < 0.05 vs. saline) and insulin resistance in mice. CAY10471 also enhanced exercise tolerance in MDX mice (100.8 ± 8.0 vs. 68.9 ± 11.1 min, P < 0.05 vs. saline) by increasing the oxidative fibre-type ratio in the muscles (45.1 ± 2.3% vs. 32.3 ± 2.6%, P < 0.05 vs. saline). CONCLUSIONS: DP2 activation suppresses oxidative fibre transition via RhoA/ROCK2/NFATc1 signalling. The inhibition of DP2 may be a potential therapeutic approach against obesity and muscle disorders.

Positive Association of TEAD1 With Schizophrenia in a Northeast Chinese Han Population.

OBJECTIVE: Schizophrenia is a complex and devastating psychiatric disorder with a strong genetic background. However, much uncertainty still exists about the role of genetic susceptibility in the pathophysiology of schizophrenia. TEA domain transcription factor 1 (TEAD1) is a transcription factor associated with neurodevelopment and has modulating effects on various nervous system diseases. In the current study, we performed a case-control association study in a Northeast Chinese Han population to explore the characteristics of pathogenic TEAD1 polymorphisms and potential association with schizophrenia. METHODS: We recruited a total of 721 schizophrenia patients and 1,195 healthy controls in this study. The 9 single nucleotide polymorphisms (SNPs) in the gene region of TEAD1 were selected and genotyped. RESULTS: The genetic association analyses showed that five SNPs (rs12289262, rs6485989, rs4415740, rs7113256, and rs1866709) were significantly different between schizophrenia patients and healthy controls in allele or/and genotype frequencies. After Bonferroni correction, the association of three SNPs (rs4415740, rs7113256, and rs1866709) with schizophrenia were still evident. Haplotype analysis revealed that two strong linkage disequilibrium blocks (rs6485989-rs4415740-rs7113256 and rs16911710-rs12364619-rs1866709) were globally associated with schizophrenia. Four haplotypes (C-C-C and T-T-T, rs6485989-rs4415740-rs7113256; G-T-A and G-T-G, rs16911710-rs12364619-rs1866709) were significantly different between schizophrenia patients and healthy controls. CONCLUSION: The current findings indicated that the human TEAD1 gene has a genetic association with schizophrenia in the Chinese Han population and may act as a susceptibility gene for schizophrenia.

The role of pregnane X receptor (PXR) in substance metabolism.

As a member of the nuclear receptor (NR) superfamily, pregnane X receptor (PXR; NR1I2) is a ligand-activated transcription factor that plays a crucial role in the metabolism of xenobiotics and endobiotics in mammals. The tissue distribution of PXR is parallel to its function with high expression in the liver and small intestine and moderate expression in the kidney, stomach, skin, and blood-brain barrier, which are organs and tissues in frequent contact with xenobiotics. PXR was first recognized as an exogenous substance receptor regulating metabolizing enzymes and transporters and functioning in detoxification and drug metabolism in the liver. However, further research revealed that PXR acts as an equally important endogenous substance receptor in the metabolism and homeostasis of endogenous substances. In this review, we summarized the functions of PXR in metabolism of different substances such as glucose, lipid, bile acid, vitamin, minerals, and endocrines, and also included insights of the application of PXR ligands (drugs) in specific diseases.

Sirtuin Family and Diabetic Kidney Disease.

Diabetes mellitus (DM) is gradually attacking the health and life of people all over the world. Diabetic kidney disease (DKD) is one of the most common chronic microvascular complications of DM, whose mechanism is complex and still lacks research. Sirtuin family is a class III histone deacetylase with highly conserved NAD+ binding domain and catalytic functional domain, while different N-terminal and C-terminal structures enable them to bind different deacetylated substrates to participate in the cellular NAD+ metabolism. The kidney is an organ rich in NAD+ and database exploration of literature shows that the Sirtuin family has different expression localization in renal, cellular, and subcellular structures. With the progress of modern technology, a variety of animal models and reagents for the Sirtuin family and DKD emerged. Machine learning in the literature shows that the Sirtuin family can regulate pathophysiological injury mainly in the glomerular filtration membrane, renal tubular absorption, and immune inflammation through various mechanisms such as epigenetics, multiple signaling pathways, and mitochondrial function. These mechanisms are the key nodes participating in DKD. Thus, it is of great significance for target therapy to study biological functions of the Sirtuin family and DKD regulation mechanism in-depth.

Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population.

Schizophrenia stands out as one of the most devastating psychiatric disorders. Previous findings have shown that schizophrenia is a polygenic genetic disorder. Thus, abnormal neurodevelopment and neurogenesis may be associated with the etiology of schizophrenia, so genes which affect these processes may be potential candidate genes of schizophrenia. Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene is a member of the mitogen-activated protein kinase family. Taking into account previous findings, MAP3K4 plays a crucial role in the fundamental pathology of various nervous system diseases. In the present study, we aim to explore the association of MAP3K4 and schizophrenia in an independent case-control sample including 627 schizophrenic patients and 1175 healthy controls from a Northeast Chinese Han population. Both the allelic and genotypic association analyses showed that 6 SNPs in MAP3K4 were significantly associated with schizophrenia (rs590988, rs625977, rs9295134, rs12110787, rs1001808 and rs9355870). After rigorous Bonferroni correction, 4 SNPs (rs9295134, rs12110787, rs1001808 and rs9355870) were still significantly associated with the disease. The haplotype composed of these four SNPs also showed significantly global and individual association with schizophrenia. These results suggest that MAP3K4 is a susceptibility gene for schizophrenia in the Northeast Chinese Han population.

miR-154-5p Affects the TGFß1/Smad3 Pathway on the Fibrosis of Diabetic Kidney Disease via Binding E3 Ubiquitin Ligase Smurf1.

AIM: The study is aimed at verifying miR-154-5p and Smurf1 combination in glomerular mesangial cells regulating TGFß1/Smad3 pathway-related protein ubiquitination in the model of diabetic rats renal tissues, primary mesangial cells, and cell lines. METHODS: The diabetic SD rat model and high-glucose-cultured primary mesangial cells and cell lines were established. miR-154-5p mimic and inhibitor, Smurf1 siRNA, and TGF ß 1/Smad3 inhibitor (SB431542) were pretreated to make the TGFß1/Smad3 pathway and ubiquitin changes. Fluorescence in situ hybridization was used for the miR-154-5p renal localization; molecular biological detection was adopted for cell proliferation, renal function, urine protein, and pathway proteins. After bioinformatics predicted binding sites, luciferase and Co-IP were used to detect miRNA and protein binding. RESULTS: miR-154-5p was significantly increased and mainly concentrated in the glomerular of renal cortex in well-established diabetic rat renal tissues. Rno-miR-154-5p combined Rno-Smurf1 3' UTR, while Smurf1 combined Smad3 directly. Meanwhile, miR-154-5p regulates TGFß1/Smad3-mediated cell proliferation via Smurf1 ubiquitination. CONCLUSION: miR-154-5p regulates the TGFß1/Smads pathway through Smurf1 ubiquitination and promotes the fibrosis process of diabetic kidney disease.

Interaction of circulating TGFß regulatory miRNAs in different severity of diabetic kidney disease.

AIMS: To explore the interaction of TGFß regulatory microRNAs (miRNAs) with different severities of diabetic kidney disease (DKD). METHODS: According to different UACR (30 and 300 mg/g), 436 subjects were included, and high glucose induced RMCs were cultured. Real-time PCR, ELISA, and automatic biochemical analysis were used to measure miRNAs, TGFß1, and other biochemical indicators in serum and RMCs. Target genes of miRNA were predicted and visualised by bioinformatics. RESULTS: HbA1c, TGFß1, miR-217, and miR-224 in T2DM patients increased with UACR, while miR-192 and miR-216a decreased. Ln UACR was positively correlated with HbA1c, TGFß1, miR-217, and miR-224, and negatively correlated with miR-192 and miR-216a. High glucose and TGFß1 affected miRNAs and these miRNAs affected each other. The miRNA target genes mainly revolve around PTEN, PI3K/Akt, and MAPK signalling pathways. CONCLUSION: TGFß regulatory miRNAs and different severity of DKD have a potential interaction regulating fibrosis through PTEN, PI3K/Akt, and MAPK pathways.

Sirtuin 6 affects glucose reabsorption and gluconeogenesis in type 1 diabetes via FoxO1.

AIM: The purpose of this study was to explore the expression changes of Sirtuin 6 in diabetic renal tissues and the molecular mechanisms affecting renal tubular gluconeogenesis and reabsorption. METHODS: The type 1 diabetic C57BL/6 mice model as well as high glucose cultured proximal tubular cells and cell lines were established. Sirt6 siRNA, the SGLT2 inhibitor (dapagliflozin), and insulin were pre-treated to make Sirtuin 6 levels, gluconeogenesis, and reabsorption changes. Immunofluorescence was used for Sirtuin 6 renal localization, and molecular biological detection was adopted for transcription factors, FoxO1, transporters (SGLT2 and GLUT2) as well as rate-limiting enzyme. Nuclear/plasma proteins were extracted to detect Sirtuin 6 and FoxO1 levels in the subcellular structure. RESULTS: Sirtuin 6 was decreased in STZ-induced diabetic renal outer medulla, and lower both in high glucose-induced primary proximal tubular cells and cell lines. Sirtuin 6 reversed the glucose reabsorption and gluconeogenesis effect via regulating FoxO1 and affecting nuclear translocation of FoxO1 in high glucose-induced proximal tubular cells. CONCLUSION: Sirtuin 6 affects renal glucose reabsorption and gluconeogenesis in type 1 diabetes by regulating FoxO1 nuclear import.

SIRT6 regulates SREBP1c-induced glucolipid metabolism in liver and pancreas via the AMPKα-mTORC1 pathway.

The aim of this study was to determine the mechanism by which SIRT6 regulates glucolipid metabolism disorders. We detected histological and molecular changes in Sprague-Dawley rats as well as in BRL 3A and INS-1 cell lines subjected to overnutrition and starvation. SIRT6, SREBP1c, and glucolipid metabolism biomarkers were identified by fluorescence co-localization, real-time PCR, and western blotting. Gene silencing studies were performed. Recombinant SIRT6, AMPK agonist (AICAR), mTOR inhibitor (rapamycin), and liver X receptor (LXR) agonist (T0901317) were used to pre-treated in BRL 3A and INS-1 cells. Real-time PCR and western blotting were used to detect related proteins, and cell counting was utilized to detect proliferation. We obtained conflicting results; SIRT6 and SREBP1c appeared in both the liver and pancreas of high-fat and hungry rats. Recombinant SIRT6 alleviated the decrease in AMPKα and increase in mTORC1 (complex of mTOR, Raptor, and Rheb) caused by overnutrition. SIRT6 siRNA reversed the glucolipid metabolic disorders caused by the AMPK agonist and mTOR inhibitor but not by the LXR agonist. Taken together, our results demonstrate that SIRT6 regulates glycolipid metabolism through AMPKα-mTORC1 regulating SREBP1c in the liver and pancreas induced by overnutrition and starvation, independent of LXR.

Endogenous fructose is correlated with urinary albumin creatinine ratios and uric acid in type 2 diabetes mellitus.

AIM: To detect the expression levels of fasting serum fructose and ketohexokinase (KHK) in patients with type 2 diabetes mellitus (T2DM) at different stages of urinary albumin creatinine ratios (UACR) and serum uric acid (sUA). METHODS: 339 T2DM patients and 107 normal volunteers were divided into the normal uric acid (275 cases) and high uric acid group (171 cases) according to uric acid levels. T2DM patients were divided into the normal albuminuria group (118 cases, UACR < 30 mg/g), microalbuminuria group (112 cases, UACR 30-300 mg/g) and large amount of albuminuria group (109 cases, UACR > 300 mg/g). Levels of fasting serum fructose and KHK were detected and statistical analysis was carried out. RESULTS: Fasting serum fructose and KHK levels increased with the increase of UACR and sUA (P < 0.05). Correlation analysis showed that fasting serum fructose and KHK levels were positively correlated with UACR and sUA (P < 0.05). Ridge regression analysis showed that fasting serum fructose and KHK were also correlated with urinary albumin and uric acid (P < 0.05). CONCLUSION: Fasting serum fructose and KHK in endogenous fructose are associated with serum uric acid and urinary albumin levels in patients with T2DM. Trial number: ChiCTR2000039870.

Association of SIRT6 circulating levels with urinary and glycometabolic markers in pre-diabetes and diabetes.

AIM: The study is aimed to detect the expression of serum Sirtuin 6 (SIRT6) with different severities and urinary albumin creatinine ratios (UACR) in type 2 diabetes mellitus (T2DM) patients, thus exploring the association of SIRT6 together with glycolipid metabolism and urinary protein in the cross-sectional study. METHODS: T2DM patients (313 cases), pre-diabetic patients (102 cases), and healthy volunteers (100 cases) were selected. T2DM patients were divided into the normal albuminuria (103 cases, UACR < 30 mg/g), micro-albuminuria (106 cases, UACR 30-300 mg/g), and large amount of albuminuria group (104 cases, UACR > 300 mg/g) based on different UACR levels. The medical history was asked, biochemical indicators were detected, hematuria samples were taken, serum SIRT6 levels were detected, and detailed statistical analysis was conducted. RESULTS: FPG, 2 h-PG, HOMA-IR, HbA1c, and LDL-C increased, while ISI and HDL-C decreased with the aggravation of diabetic status (P < 0.05). HbA1c, UACR, TNFα, HIF1α, and SIRT6 increased with UACR in T2DM patients (P < 0.05). Correlation analysis demonstrated that SIRT6 was significantly positively correlated with glycolipid metabolism in the whole samples, and correlated with UACR, TNFα, and HIF1α in T2DM patients (P < 0.05). Ridge regression analysis showed that SIRT6 was a risk factor for both glycolipid metabolism and urinary protein (P < 0.05). CONCLUSION: SIRT6 increases with biomarkers in glycolipid metabolism and urinary protein in different severities of diabetes and UACR, which is expected to be a potential biomarker for early prediction and diagnosis related to glycolipid metabolism disorders and related nephropathy. Trial number: ChiCTR2000039808.

RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis.

The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer. In TNBC, Aquaporin 1 (AQP1), a water-transporting transmembrane protein, is aberrantly enriched in cytoplasm and causes tumor cell death evasion. However, the carcinogenetic bioactivities of cytoplasmic AQP1 cannot be attributed to the canonical "osmotic engine model". In the present study, the receptor-interacting protein kinase 1 (RIPK1), a cell death regulator, was identified to negatively mediate AQP1-driven TNBC progression and metastasis. AQP1 overabundance and RIPK1 depletion occurred in TNBC, which were correlated with aggressive oncological features and poor prognosis. AQP1 bound with RIPK1, resulting in the inhibition of RIPK1/RIPK3/MLKL-mediated necroptosis and RIPK1/caspase-8/caspase-3-mediated apoptosis. Genetic inhibition of RIPK1 significantly exacerbated the pro-tumor effect of AQP1, while ectopic expression of RIPK1 notably blunted AQP1 signaling. Mechanistically, AQP1 binds to the D324 site of RIPK1, and facilitates RIPK1 cleavage and inactivation by excessively activating the caspase-8/RIPK1 negative feedback loop. RIPK1D324K overexpression significantly prevented RIPK1 cleavage and weakened the aggressiveness of AQP1-enriched TNBC cells. Overall, our findings clarify the underlying mechanism of cytoplasmic AQP1-driven TNBC progression and metastasis, in which RIPK1 exerts an essential role as a negative mediator and exhibits the potential as a therapeutic target for TNBC.