AIM:Renal fibrosis is a major contributor to chronic kidney disease (CKD) progression and eventual organ failure. G protein-coupled bile acid receptor 1 (TGR5) was previously shown to have beneficial effects on kidney diseases. The current study aimed to investigate whether TGR5 activation prevents kidney fibrosis and to clarify the underlying mechanism. METHODS:TGR5 expression was examined in human fibrotic kidneys. Two animal models of renal fibrosis were used: unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury with contralateral nephrectomy (uIRIx) in wild-type and TGR5 knockout mice. Renal histology, extracellular matrix (ECM) deposition, and renal function were examined. In vitro studies were performed on human proximal tubular HK2 cells by treating them with transforming growth factor-β1 and TGR5 agonists/antagonists. RESULTS:TGR5 was significantly downregulated in fibrotic human kidneys. In both UUO and uIRIx models, TGR5 activation by lithocholic acid alleviated renal fibrosis, reduced ECM deposition, and improved kidney function. Conversely, Tgr5 knockout in mice exacerbated fibrotic injury. Mechanistically, TGR5 activation prevented fibrosis development, probably by enhancing NEDD4L-mediated ubiquitination and degradation of phosphorylated Smad2/3 by inhibiting the upstream PI3K-SGK1 pathway. CONCLUSION:TGR5 activation protects against renal fibrosis by inhibiting the PI3K-SGK1-NEDD4L axis and promoting p-Smad2/3 degradation.

Renal fibrosis is the terminal pathological manifestation of most chronic kidney diseases. The phosphodiesterase type 5 (PDE5) inhibitors have shown therapeutic potentials in a wide array of chronic conditions. LW1646 is a newly identified inhibitor with high specificity and potency against PDE5. The current study aims to investigate the therapeutic effects of LW1646 on renal fibrosis and its underlying mechanisms. mRNA and protein expression level of PDE5 was elevated in renal cortex of mice with unilateral ureter obstruction for seven days (7UUO). LW1646 effectively suppressed pro-fibrotic responses in TGF-β1-stimulated HK-2 cells as well as in mice with 7UUO-induced renal fibrosis. Genetic deletion or knockdown of Pde5a produced similar antifibrotic benefits. Mechanistically, both PDE5 inhibition with LW1646 and Pde5a knockout alleviated ER stress and mitigated mitochondrial dysfunction, as evidenced by restored mitochondrial biogenesis, suppression of excessive fragmentation, preservation of membrane potential, and reduction of oxidative stress. Further investigation revealed that ER stress-driven mitochondrial injury involved augmented mitochondria associated membrane (MAM) formation, characterized by increased expression of the hallmark IP3R1-GRP75-VDAC1 complex. This enhanced interaction facilitated excessive calcium transfer from the ER to mitochondria, culminating in mitochondrial calcium overload. PDE5 inhibition effectively suppressed MAM formation and reduced mitochondrial calcium accumulation, thereby maintaining mitochondrial homeostasis under fibrotic stress. Collectively, these findings identify activation of cGMP-PKG signaling by LW1646 as a promising therapeutic pathway for renal fibrosis through suppression of ER stress and stabilization of mitochondrial homeostasis.

Renal ischemia-reperfusion (IR) injury is a major cause of acute kidney injury (AKI), with limited specific therapies. Recombinant human brain natriuretic peptide (rhBNP) shows potential renal protective effects, but its role and mechanism in IR-induced AKI is unclear. The present study showed rhBNP improved renal function recovery and reduced AKI progression in ICU patients. In rat IR models, rhBNP alleviated tubular injury and enhanced kidney function. Selenocysteine lyase (SCLY), an enzyme critical for selenium recycling and selenoprotein synthesis, was identified as the hub gene associated with rhBNP treatment by transcriptome sequencing. rhBNP treatment markedly upregulated the expression of SCLY in rat kidneys with elevated selenium levels. rhBNP also inhibited ferroptosis and apoptosis in the kidney, which was significantly reversed by the knockdown of SCLY. SCLY silencing blocked the protective effect of rhBNP on human HK2 cells subjected to CCCP-R (carbonyl cyanide 3-chlorophenylhydrazone induced ATP depletion-repletion), while SCLY overexpression enhanced it. rhBNP modulated SCLY expression likely through inhibiting the binding of active GTPase RhoA to SCLY protein. In conclusion, rhBNP prevented IR-induced AKI through inhibiting ferroptosis by upregulating SCLY level and promoting selenium recycling, presenting a potentially new target for AKI treatment.

Renal fibrosis is the terminal pathological manifestation of most chronic kidney diseases (CKDs). Inhibitors targeting phosphodiesterase 5 (PDE5) have been used to treat erectile dysfunction and pulmonary arterial hypertension by increasing cGMP levels and activating the cGMP/PKG signaling pathway. Studies have shown that PDE5 inhibitors can attenuate the progression of CKD, although the underlying mechanisms remain unclear. LW1646 is a newly identified inhibitor with higher specificity and potency against PDE5. This study aims to investigate the therapeutic effects of LW1646 on renal fibrosis and its underlying mechanisms. In vitro, pro-fibrotic response in HK2 cells was induced by TGF-β1 and intervened with LW1646. In vivo, renal interstitial fibrosis model was established by unilateral ureteral obstruction for 7 days (7UUO) in Pde5a-/- mice. mRNA expression level of Pde5a was analyzed by qPCR. Western blot was used to assess changes in fibrosis markers, endoplasmic reticulum stress indicators, mitochondrial homeostasis metrics, and components of mitochondrial-associated membranes (MAM). Mitochondrial membrane potential (MMP) and reactive oxygen species were evaluated using flow cytometry, fluorescent imaging was employed to visualize mitochondrial networks, accumulation of mitochondrial calcium (mtCa2+) and formation of MAM. Histological assessments of renal fibrosis were performed using H&E staining and Masson's trichrome staining. Morphology of mitochondria and ER and mitochondria-ER contact in kidney cortex were investigated by transmission electron microscope (TEM). mRNA expression level of Pde5a was elevated in renal cortex in 7UUO-induced kidney fibrosis mice. Expression of fibrosis markers and endoplasmic reticulum stress indicators were markedly upregulated both in vitro and in vivo. Meanwhile, mitochondrial biogenesis was inhibited, which was accompanied by increased oxidative stress, decreased MMP and augmented mitochondrial fission. MAMs formation and mtCa2+ level were enhanced. LW1646 significantly prevented development of fibrosis in mice with 7UUO and exhibited a more pronounced effect than sildenafil. Pde5a knockout was associated with alleviated fibrosis in mice. LW1646 or Pde5a knockout attenuated ER stress and altered mitochondrial homeostasis in fibrotic kidneys and HK2 cells exhibiting pro-fibrotic responses. Our data demonstrated that LW1646 ameliorated renal fibrosis likely through inhibiting ER stress and maintaining mitochondrial homeostasis. Mechanistically, activation of cGPM/PKG pathway by LW1646 or Pde5a knockout conferred mitochondrial protection by inhibiting the formation of MAMs, thereby reducing mtCa2+ overload and alleviating renal fibrosis.

Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, is responsible for the reabsorption of sodium and plays a critical role in the regulation of extracellular fluid volume and consequently blood pressure. The G protein-coupled bile acid receptor (TGR5) is a membrane receptor mediating effects of bile acid and is implicated in kidney diseases. The current study aims to investigate whether TGR5 activation in the kidney regulated ENaC expression and potential mechanism. Lithocholic acid (LCA), a TGR5 agonist, markedly decreased systolic blood pressure induced by DOCA-salt in mice, which was associated with decreased ENaC expression in the kidney. DOCA-salt treatment increased renal expression of histone H3 lysine 4 trimethylation (H3K4me3) and decreased expression of lysine-specific demethylase 5A (KDM5A), a lysine demethylase, which was markedly reversed by LCA. TGR5 knockout caused further increased systolic blood pressure and ENaC expression in mice with DOCA-salt in association with increased H3K4me3 and decreased KDM5A. In immortalized mouse cortical collecting duct (mpkCCD) cells LCA markedly inhibited aldosterone-induced ENaC-mediated current. LCA treatment or TGR5 overexpression markedly inhibited ENaC and H3K4me3 protein expression in association with decreased KDM5A in mpkCCD cells treated with either aldosterone or angiotensin II. Inhibition or knockdown of KDM5A in mpkCCD cells prevented LCA-induced downregulation of ENaC expression by promoting H3K4me3 on the ENaC transcription start site. LCA upregulated KDM5A expression was likely through JNK/c-Jun signal pathway. In conclusion, LCA decreased blood pressure and ENaC protein expression in the kidney of mice with DOCA-salt, likely through activating TGR5 and upregulating KDM5A-induced H3K4me3 demethylation in ENaC promoter region.

Cardiac telerehabilitation is proven to be equally safe and effective as center-based cardiac rehabilitation. Nevertheless, some real-world barriers significantly impact the adoption and successful implementation of cardiac rehabilitation as well as cardiac telerehabilitation. This study assesses willingness and actual participation in cardiac (tele)rehabilitation, examining key influencing factors (i.e. digital health readiness, health literacy, patients’ awareness). It explores the relation between digital health readiness and patients’ awareness concerning their intention to participate in cardiac telerehabilitation. Additionally, it investigates the relation between intention and actual participation in cardiac rehabilitation, considering the impact of health literacy and patients’ awareness. In this prospective single-center survey study, patients with cardiovascular disease were asked to fill in questionnaires. Digital health readiness was measured by Digital health readiness questionnaire (DHRQ), and health literacy was assessed with the Health Literacy Scale (HLS-EU). Patients' awareness of their cardiovascular disease was determined by the accuracy of their understanding of their specific cardiovascular condition. A total of 72 patients (mean age 62.7 ± 13.3; 33.3% is women) were included in this survey. 81.7% and 50% patients have respectively the intention to participate in cardiac rehabilitation and telerehabilitation. Additionally, 50,7% patients actually participated cardiac rehabilitation. There is a negative correlation between age and digital health readiness (r = -0.05, p < 0.001)/learnability ( r= -0.26, P = 0.025). There is no correlation between digital health readiness (r= 0.011, P= 0.931) and patients’ awareness with the intention to participate in cardiac telerehabilitation (r = -0.045, P = 0.733). Furthermore, there is also no correlation between health literacy (r = 0.196, P= 0.123) and patients’ awareness (r = 0.002, P = 0.086) with the intention to participate in cardiac rehabilitation. Lastly, no correlation between health literacy and actual participation in cardiac rehabilitation is detected (r = -0.115, P = 0.375), but it has been established that there is a relationship between patients’ awareness and actual participation in cardiac rehabilitation (r = -0.266, P = 0.033). Cardiovascular patients express a moderate intention to participate in cardiac terehabilitation, and there is no relation between digital health readiness and this intention, suggesting that digital health readiness is not a barrier to the willingness to participate cardiac telerehabilitation. Additionally, higher levels of patients’ awareness of their cardiovascular disease appears to result in increased engagement in cardiac rehabilitation program. However, further research is necessary to explore the barriers in participation to cardiac (tele)rehabilitation.

Abstract Background Digital health has been increasingly applied to the cardiovascular field, especially since the COVID era. Japan is a super-aged society with an average life expectancy of 81 years for men and 87 years for women in 2023. However, there are no existing tools to measure digital health readiness and learnability to implement "digital cardiology" in such a society. Purpose The purpose of this study is to validate the Japanese translation of the Digital Health Readiness Questionnaire (DHRQ) created in Belgium to assess the digital readiness of Japanese patients with cardiovascular disease. Methods A multicentre cross-sectional study of 210 patients with cardiovascular disease in Kawasaki, an urban, aging city, was conducted at a university hospital and a city hospital. Regarding the translation of the DHRQ, the back translation method was used and the differences between the translated version and the original version were discussed. The DHRQ consists of the DHRQ score and the learnability score. Multivariate analysis and confirmatory factor analysis were performed. Results A total of 208 complete questionnaires were included in the analysis. The average age was higher than in Belgium (68 ± 14 vs. 62 ± 15 years), of which 82 (39%) were female. The highest age was 96 and the lowest was 24. Smartphone ownership was higher than in Belgium (86% vs. 81%), but smartwatch and PC ownership was lower than in Belgium (18% vs. 28% and 54% vs. 87%). In multiple regression analysis, age, education level, and smartphone ownership were significant predictors of DHRQ and learnability scores (p ≤ 0.001), while gender and income were not significant predictors. Cronbach's alpha analysis was above 0.8 for all domains of the DHRQ, which implied acceptable internal consistency. The fit indices of the confirmatory factor analysis (Table) showed good fit. The goodness of fit improved when one topic of digital usage with low factor loading ("I use a wearable.") was removed. Conclusion In Japan, a super-aged society, the trend is almost the same as in Belgium, and DHRQ can be used. The introduction of digital cardiology needs to be individualized, paying attention to age, education level (the higher the better), and smartphone ownership (but not dependent on income).

Abstract Background Physical activity plays a crucial role in cardiac rehabilitation for secondary prevention. Despite its importance, participation rates in cardiac rehabilitation programs remain low. Telemedicine, particularly telerehabilitation, presents a viable solution by offering remote access to cardiac rehabilitation services. This innovative approach has the potential to significantly enhance patient outcomes. Purpose This study aimed to assess the effectiveness of digital health intervention in improving physical activity in cardiac rehabilitation center. Methods A prospective randomised controlled trial was conducted, enrolling 80 eligible cardiac rehabilitation patients. Participants were 1:1 randomised into two groups: a 12-week center-based cardiac rehabilitation program (control group), and a 12-week center-based cardiac rehabilitation program combined with a digital health intervention (intervention group). This digital health intervention consists of smartphone, web, and tablet applications to monitor physical activity outside of rehabilitation sessions and motivate patients to engage in more physical activities. Results Of the initial 80 patients, 70 completed the study, and the results are presented in Table 1. In the intervention group, there was a statistically significant improvement in peak rate of oxygen consumption (VO2 peak) (p < 0.01) and peak power output (W peak) (p < 0.01), as measured by cardiopulmonary exercise testing between the end and the beginning of the study at the significance level of 0.05. Similar improvements were also observed in the control group (p = 0.0002 for VO2 peak and p < 0.01 for W peak). After 12 weeks of intervention, significant between-group differences were found: We observe a greater improvement in VO2 peak, on average 1.39 (95% CI: 0.23-2.54) ml/kg, and in W peak, on average, 12.29 (95% CI: 4.12-20.45), higher in the intervention group compared to the control group. Regarding physical activity, the intervention group showed a significant improvement in step count (P = 0.002), measured by an accelerometer, whereas no significant improvement was observed in the control group (P = 0.9714). There is a statistically significant difference in the change of step count between the intervention and control group at the significance level of 0.05. We observe a greater improvement, on average 14 788 steps (95% CI: 4 246 – 25 331), in the intervention group compared to the control group. Conclusion This study shows that a combination of a digital health intervention based telerehabilitation with a center-based cardiac rehabilitation is more effective in increasing patient’s exercise capacity and physical activity compared with a center-based cardiac rehabilitation.Table 1:results

目的探讨激活胆汁酸受体TGR5在单肾缺血再灌注损伤合并对侧肾摘除（uIRIx）模型诱导的肾脏纤维化中的作用。方法体内实验：将C57BL/6J小鼠随机分成假手术（Sham）组、uIRIx组及uIRIx+石胆酸（LCA）组，每组6只，使用uIRIx模型诱导肾脏纤维化，通过血和尿生化指标评估肾脏功能，利用HE染色评估肾脏损伤程度，使用Masson染色及免疫组化对肾脏纤维化程度进行评估，并用Western Blotting检测肾脏皮质纤维化相关指标蛋白表达；分别在TGR5+/+小鼠及TGR5-/-小鼠中设置Sham组及uIRIx组，每组6只，利用Western Blotting检测各组肾脏纤维化程度。体外实验：在人源肾上皮细胞系HK2细胞中给予TGF-β1诱导促纤维化反应，给予LCA进行药物干预，利用鬼笔环肽染色标记细胞骨架，使用Western Blotting检测HK2细胞内纤维化相关指标蛋白表达。结果体内实验：与Sham组相比，uIRIx组小鼠血浆肌酐水平（P=0.007）及尿白蛋白/肌酐比（P=0.041）明显增加，肾脏皮质蛋白TGR5表达（P=0.002）下降，Fibronectin表达（P=0.020）及COL1A1表达（P<0.001）上升，同时伴有肾脏结构受损及胶原沉积加重，LCA干预有效改善肾脏功能，缓解肾脏损伤及纤维化程度；TGR5+/+小鼠与TGR5-/-小鼠相比，uIRIx诱导引起的Fibronectin表达（P<0.001）及COL1A1表达（P=0.001）增加。体外实验：TGF-β1诱导HK2细胞形态改变，细胞骨架解聚重组，促纤维化指标蛋白上调；LCA可有效抑制TGF-β1诱导的细胞形态改变及骨架解聚重组，呈浓度依赖性下调纤维化相关指标蛋白表达。结论LCA缓解uIRIx模型诱导的肾脏纤维化，TGR5基因敲除加重uIRIx诱导的肾脏纤维化；在HK2细胞中，LCA缓解TGF-β1诱导的细胞促纤维化反应。研究结果提示激活TGR5缓解缺血再灌注后肾脏纤维化损伤进程。

Renal medullary aquaporin-1 (AQP1) plays an important role in the urinary concentration. This study aimed to investigate the regulation of AQP1 by low osmotic stress and a potential role of autophagy. Low osmotic stress induced a dramatically decreased AQP1 protein expression in murine inner medullary collecting duct 3 (mIMCD3) cells, which was associated with a marked activation of autophagy. Inhibition of autophagy by 3-methyladenine (3-MA), chloroquine, or knockdown of autophagy-related protein 5 (ATG5) prevented the decrease in AQP1 protein abundance. Rapamycin-induced autophagy was associated with a decreased AQP1 protein expression and an enhanced interaction between AQP1 and ATG5 in mIMCD3 cells under low osmotic stress. In kidney inner medulla of mice given a 3% NaCl solution, activation of autophagy was associated with decreased AQP1 protein expression, which was prevented by 3-MA. In conclusion, low osmotic stress induced autophagy which contributed to the decreased AQP1 protein expression in the renal medulla.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): FWO - Flanders Research Foundation. Background/Introduction The international classification of disease (ICD) codes are used worldwide for classification of hospitalisations. The codes are used for administrative, financial and research purposes. It is known however that errors occur in the coding process. Purpose To investigate methods for automatic classification of disease in unstructured medical records using natural language processing (NLP) and to compare these to conventional ICD-10 coding. Methods Two datasets were used: the open-source Medical Information Mart for Intensive Care (MIMIC)-III dataset (n=40.000) for algorithm testing and a dataset from a hospital in Belgium (n = 8041). In the Belgian dataset automated pseudonymization was performed prior to further analysis. A training, validation and test set was used in all methods. Automated searches using NLP algorithms were performed for the diagnoses "atrial fibrillation" and "heart failure". The information extraction methods that were used were: rule-based search, logistic regression, term frequency-inverse document frequency (TF-IDF), XGBoost and bio-bidirectional encoder representations from transformers (BioBERT). All algorithms were tested on the MIMIC-III dataset. Precision (or positive predictive value), recall (or sensitivity) and accuracy were calculated for each model. The best performing algorithm was then deployed on the Belgian dataset. Results and discussion Results for the different NLP models are depicted in Table 1. Non-compatible results in NLP versus ICD-coding often indicated errors in ICD-coding. NLP algorithms could thus be used to improve the ICD-coding process in hospitals. Conclusion A high accuracy can be achieved when using NLP algorithms for diagnostic classification of patient records. Also, NLP algorithms can be used to identify ICD-coding errors and optimise the ICD-coding process.

Hyperhomocysteinemia is a risk factor for various cardiovascular diseases. However, the mechanism underlying homocysteine- (Hcy-) induced vascular injury remains unclear. The purpose of the present study was to examine a potential mechanism by which Hcy induced injury in human umbilical vascular endothelial cells (HUVEC). The protein abundance of autophagy-related markers was markedly decreased after Hcy treatment, which was associated with endoplasmic reticulum (ER) stress and apoptosis in HUVECs. Protein expression level of angiotensin II type 1 receptor (AT1 receptor) was dramatically increased in response to Hcy. Valsartan, an AT1 receptor blocker, improved autophagy and prevented ER stress and apoptosis in HUVECs treated with Hcy. Consistent with this, silence of AT1 receptor with siRNA decreased the protein abundance of ER stress markers, prevented apoptosis, and promoted autophagy in HUVECs. Inhibition or knockdown of AT1 receptor was shown to be associated with suppression of p-GSK3β/GSK3β-p-mTOR/mTOR signaling pathway. Additionally, inhibition of autophagy by 3-MA aggravated Hcy-induced apoptosis, while amelioration of ER stress by 4-PBA prevented Hcy-induced injury in HUVECs. Hcy-induced HUVEC injury was likely attributed to AT1 receptor activation, leading to impaired autophagy, ER stress, and apoptosis.

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy characterized by massive fibrosis and has ineffective adjuvant therapies. Here, we demonstrate the potential of angiotensin receptor blockers (ARBs) in targeting iCCA. Methods Masson's trichrome staining was used to assess the effect of ARBs in iCCA specimens, CCK8 and gel contraction assays in vitro and in xenograft models in vivo. RNA‐seq and ATAC‐seq were used for mechanistic investigations. Results Patients with iCCA who were administered ARBs had a better prognosis and a lower proportion of tumour stroma, indicating alleviated fibrosis. The presence of AGTR1, the ARBs receptor, is associated with a poor prognosis of iCCA and is highly expressed in tumour tissues and cancer‐associated fibroblasts (CAFs). The ARBs strongly attenuated the viability of AGTR1+CAFs in vitro and retarded tumour progression and fibrosis in xenograft models of co‐cultured CAFs and iCCA cells. Still, they did not have a significant effect on AGTR1−CAFs. Moreover, ARBs decreased the secretion of AGTR1+CAF‐derived MFAP5 via the Hippo pathway, weakened the interaction between CAFs and iCCA cells, and impaired the aggressiveness of iCCA cells by attenuating the activation of the Notch1 pathway in iCCA cells. Conclusions ARBs exhibit anti‐fibrotic function by inhibiting the viability of AGTR1+CAFs. These findings support using ARBs as a novel therapeutic option for targeting iCCA.

Aquaporins (AQPs) are a family of membrane water channels that basically function as regulators of intracellular and intercellular water flow. To date, 13 AQPs, distributed widely in specific cell types in various organs and tissues, have been characterized in humans. A pair of NPA boxes forming a pore is highly conserved among all aquaporins and is also key residues for the classification of AQP superfamily into four groups according to primary sequences. AQPs may also be classified based on their transport properties. So far, chromosome localization and gene structure of 13 human AQPs have been identified, which is definitely helpful for studying phenotypes and potential targets in naturally occurring and synthetic mutations in human or cells.

Abstract Funding Acknowledgements Type of funding sources: None. Background Telemonitoring is an intervention that has shown to improve care of heart failure (HF) patients and thus plays a major role in preventing frequent hospital visits. Purpose This study examined the impact of HF telemonitoring on unplanned hospitalization. Methods Patients admitted to the hospital for HF and who agreed to use the non-invasive telemonitoring system were candidates in the study. It measured body weight, blood pressure and heart rate each day, and an alert was made if they exceeded a certain limit. The study contained data from 97 patients. The primary endpoint was a composite of unplanned cardiovascular hospitalization and all-cause mortality. Patients were classified into three groups: hospitalized (for any of the endpoints) during the telemonitoring period (Group 1 ["monitoring failure"]), hospitalized after the telemonitoring period (Group 2), and not hospitalized (Group 3). Results Median telemonitoring period was 222 [141, 518] days. The number of patients in each group was 18, 18, and 61. Patients in Group 1 were older (75 vs. 63 years, p < 0.001) and had poorer estimated glomerular filtration rate (31 vs. 62 mL/min/1.73m2, p < 0.001) than those in Group 3. Length of hospitalization periods at the endpoint tended to be longer in Group 1 than Group 2 (8.5 [6, 14] vs. 5 [4, 10] days, p = 0.084). Conclusion If heart failure telemonitoring fails to prevent unplanned hospitalization, the length of that hospitalization period may be longer than if the unplanned hospitalization could have been prevented.

In the past few decades, advances in the outcomes of patients suffering from pancreatic ductal adenocarcinoma (PDAC) have lagged behind these gained in the treatment of many other malignancies. Although the pivotal role of the SUMO pathway in PDAC has been illustrated, the underlying molecule drivers have yet to be fully elucidated. In the present study, we identified SENP3 as a potential suppressor of PDAC progression through an in vivo metastatic model. Further studies revealed that SENP3 inhibited PDAC invasion in a SUMO system dependent fashion. Mechanistically, SENP3 interacted with DKC1 and, as such, catalyzed the deSUMOylation of DKC1, which accepted SUMO3 modifiers at three lysine residues. SENP3-mediated deSUMOylation caused DKC1 instability and disruption of the interaction between snoRNP proteins, which contributed to the impaired migration ability of PDAC. Indeed, overexpression of DKC1 abated the anti-metastasis effect of SENP3, and DKC1 was elevated in PDAC specimens and associated with a poor prognosis in PDAC patients. Collectively, our findings shed light on the essential role of SENP3/DKC1 axis in the progression of PDAC.