OBJECTIVE To form an expert consensus on the clinical application of parenteral direct thrombin inhibitors （DTIs） in patients during the perioperative period. METHODS Led by Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital （the Affiliated Hospital of UESTC）， a multidisciplinary working group was established. Through literature review and the Delphi method， clinical questions related to the rational perioperative use of parenteral DTIs were identified. A structured design was adopted using the “Population-Intervention-Comparison-Outcome” framework； systematic searches were conducted in CNKI， Medline， Embase and other databases. Relevant evidence from randomized controlled trials and cohort studies was included and synthesized. Evidence quality was assessed using the Grades of Recommendations Assessment，Development and Evaluation （GRADE） approach， and recommendations were formulated through multiple rounds of Delphi surveys and expert consensus meetings. RESULTS &CONCLUSIONS Seven recommendations （each with an expert consensus rate exceeding 90%） on the use of parenteral DTIs in perioperative patients were developed. These recommendations specify drug selection， dosing ranges， key monitoring points， and safety management strategies for parenteral DTIs in various scenarios， including the perioperative period of ventricular assist device implantation， the perioperative period of cardiac surgery， perioperative patients with lower-extremity atherosclerotic disease， the perioperative period of percutaneous coronary intervention in patients with acute coronary syndrome， the perioperative period of carotid artery stenting in patients with carotid stenosis， the perioperative period of patients with right heart thrombosis， and patients who develop related thrombosis and dysfunction after a central venous catheter insertion. In addition， warning and management pathways for perioperative bleeding and thrombotic events were proposed. This expert consensus， which is formulated based on the best available evidence， provides evidence-based guidance for standardized and individualized use of parenteral DTIs in perioperative period.

OBJECTIVE: To assess the association of microribonucleic acid (miRNA) gene polymorphisms with the risk and clinicopathological characteristics of Crohn's disease (CD) and the influence of miRNA gene variants on the response to ustekinumab (UST) treatment among CD patients. METHODS: From January 2018 to February 2025, 312 patients diagnosed with CD and 527 gender- and age-matched normal controls were selected as the study subjects at the Department of Gastroenterology of the Second Affiliated Hospital of Wenzhou Medical University. Genotypes of miR-155 (rs767649), miR-21 (rs13137), miR-124 (rs531564) and miR-146a (rs57095329, rs2431697) were determined with multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) technique. The patients were divided into different subgroups according to the Montreal Classification Criteria for CD. Harvey-Bradshaw index (HBI) and simplified endoscopic score for CD were respectively applied to assess the clinical and endoscopic disease activity of CD. Unconditional logistic regression model was employed to analyze the distribution of miRNA gene polymorphisms between the two groups, as well as their influence on the clinicopathological characteristics of CD patients. Among them, 185 CD patients received first-line UST treatment, with the first sufficient dose of UST (6 mg/kg) administered intravenously. Based on the changes in HBI at week 8, the response of patients to UST treatment was evaluated. Unconditional logistic regression model was employed to analyze the distribution of miRNA gene polymorphisms between clinically responsive group (the decline of HBI ≥ 3 scores compared to week 0) and non-responsive group. All of the P values were adjusted by Bonferroni correction. This study has been approved by the Medical Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University (Ethics No.: 2025-K-12-01). RESULTS: No significant difference was found in the distribution of miRNA gene polymorphisms between the two groups (all P > 0.05). The variant genotype (TC+CC) of rs2431697 was more common among patients with terminal ileal-type and ileocolic-type CD than those with the colonic-type CD (OR = 4.98, 95%CI: 1.49~16.68, P = 0.009, adjusted P = 0.045). However, the opposite conclusion was drawn for the homozygous variant genotype (TT) of rs13137 and variant genotype (GC+CC) of rs531564 (OR = 0.37, 95%CI: 0.18~0.76, P = 0.007, adjusted P = 0.035; OR = 0.36, 95%CI: 0.18~0.73, P = 0.004, adjusted P = 0.020). Compared to patients with non-stricturing and penetrating CD, the variant genotype (AG+GG) and variant allele (G) of rs57095329 were more common in those with stricturing and penetrating CD (OR = 4.06, 95%CI: 2.46~6.71, P < 0.001, adjusted P < 0.005; OR = 3.12, 95%CI: 2.06~4.73, P < 0.001, adjusted P < 0.005). However, the frequencies of variant genotype (AT+TT) and variant allele (T) of rs13137 were lower among patients with stricturing and penetrating CD than in those without (OR = 0.25, 95%CI: 0.15~0.41, P < 0.001, adjusted P < 0.005; OR = 0.45, 95%CI: 0.33~0.63, P < 0.001, adjusted P < 0.005). Additionally, the variant genotype (AG+GG) and variant allele (G) of rs57095329 were more common among those with moderately to severely endoscopic activity than those with mildly endoscopic activity (OR = 2.01, 95%CI: 1.19~3.42, P = 0.009, adjusted P = 0.045; OR = 2.04, 95%CI: 1.28~3.25, P = 0.003, adjusted P = 0.015). In total 117 cases had shown clinical response by week 8, while 68 cases showed no response. Compared with t he clinically non-responsive group, the variant genotype (TC+CC) and variant allele (C) of rs2431697 were more common in the clinically responsive group (OR = 3.86, 95%CI: 1.80~8.32, P = 0.001, adjusted P = 0.005; OR = 2.60, 95%CI: 1.34~5.06, P = 0.005, adjusted P = 0.025). However, the variant genotype (TA+AA) of rs767649 was less frequent in the clinically responsive group than the non-responsive group (OR = 0.40, 95%CI: 0.21~0.74, P = 0.004, adjusted P = 0.020). The same conclusion was drawn for the variant genotype (AT+TT) and variant allele (T) of rs13137 when the clinically responsive group was compared with the non-responsive group (OR = 0.30, 95%CI: 0.14~0.63, P = 0.002, adjusted P = 0.010; OR = 0.54, 95%CI: 0.35~0.82, P = 0.005, adjusted P = 0.025). CONCLUSION Genetic polymorphisms of miRNAs are not associated with the risk of developing CD. The miR-146a (rs57095329) variant may increase the endoscopic activity of CD and the risk for stenosis or penetration. However, the miR-146a (rs2431697) variant may increase the risk of ileal involvement. The miR-21 (rs13137) variant may reduce the risk of ileal involvement and the risk of stenosis or penetration. The miR-124 (rs531564) variant may reduce the risk of ileal involvement. Among patients receiving UST treatment, the miR-146a (rs2431697) variant may increase the clinical response by week 8. However, both the miR-155 (rs767649) and miR-21 (rs13137) variants may decrease the clinical response by week 8.
Humans ; MicroRNAs/genetics* ; Crohn Disease/pathology* ; Male ; Female ; Adult ; Polymorphism, Single Nucleotide ; Middle Aged ; Asian People/genetics* ; Genetic Predisposition to Disease ; Genotype ; Young Adult ; Case-Control Studies ; Adolescent ; East Asian People

Objective To compare the dosimetric differences, plan complexity, verification pass rate, and execution efficiency of volumetric modulated arc therapy (VMAT) plans designed for post-mastectomy radiotherapy of breast cancer using Halcyon 2.0 and VitalBeam accelerators in flattening filter-free mode. Methods A retrospective analysis was conducted on imaging data from 87 female breast cancer patients aged 29 to 75 (49.9 ± 9.9) years who underwent modified radical mastectomy followed by radiotherapy. VMAT plans were designed using both VitalBeam and Halcyon accelerators in flattening filter-free mode. The dosimetric parameters, plan complexity, verification pass rate, and execution efficiency were compared between the plans designed for both accelerators, with a significance level of P<0.05. Results In terms of target volume parameters, Halcyon 2.0 plans demonstrated superior homogeneity index and conformity index. For organs at risk, the Halcyon 2.0 plans showed lower doses for the lungs (D_20% and D_mean) and heart (D_mean) compared to the VitalBeam plans (all P<0.05). Regarding plan complexity, Halcyon 2.0 plans exhibited better median average aperture area variation (0.35 ± 0.02), smaller aperture score, and larger median plan aperture area than VitalBeam plans (all P<0.05). However, VitalBeam plans had a superior median modulation complexity score (0.28 ± 0.01) compared to Halcyon 2.0 plans (P<0.05). Patient plans were assessed using the ArcCHECK phantom, revealing higher pass rates and significantly shorter execution time for Halcyon plans compared to VitalBeam plans (P<0.05). Conclusion Both Halcyon 2.0 and VitalBeam accelerators can provide high-quality VMAT plans for postoperative radiotherapy of breast cancer, with excellent verification pass rates ensuring treatment accuracy and efficacy. However, Halcyon 2.0 offers lower plan complexity, simplifies the treatment planning process, and reduces execution time, thereby achieving higher treatment efficiency and demonstrating greater advantages in clinical applications.

Under the current upsurge of cross-disciplinary research between artificial intelligence （AI） and traditional Chinese medicine （TCM）， the inheritance of academic thought in TCM is confronted with the deep-seated predicament of cognitive paradigm dislocation. The existing AI model is based on the classical reasoning mode of formal logic and statistical probability， which is difficult to adapt to the nonlinear and holistic cognitive logic of TCM with image-based thinking and syndrome-differentiated treatment as the core， resulting in systematic misreading and loss of the core essence in digital inheritance. Based on this， this paper proposes to construct a new cognitive model oriented towards the context of TCM. Its essence is not to have AI imitate the thinking of TCM， but to establish an auxiliary understanding framework based on semantic mapping and relational reasoning. It is advocated that the role of AI should be reconstructed from a knowledge substitute to a clinical interactor， and its application boundary in the inheritance of TCM wisdom should be clarified. By establishing the theoretical framework and practical path of human-computer collaboration， this paper aims to provide a scientific basis for realizing the deep integration of AI technology and the academic thought in TCM.

Under the current upsurge of cross-disciplinary research between artificial intelligence （AI） and traditional Chinese medicine （TCM）， the inheritance of academic thought in TCM is confronted with the deep-seated predicament of cognitive paradigm dislocation. The existing AI model is based on the classical reasoning mode of formal logic and statistical probability， which is difficult to adapt to the nonlinear and holistic cognitive logic of TCM with image-based thinking and syndrome-differentiated treatment as the core， resulting in systematic misreading and loss of the core essence in digital inheritance. Based on this， this paper proposes to construct a new cognitive model oriented towards the context of TCM. Its essence is not to have AI imitate the thinking of TCM， but to establish an auxiliary understanding framework based on semantic mapping and relational reasoning. It is advocated that the role of AI should be reconstructed from a knowledge substitute to a clinical interactor， and its application boundary in the inheritance of TCM wisdom should be clarified. By establishing the theoretical framework and practical path of human-computer collaboration， this paper aims to provide a scientific basis for realizing the deep integration of AI technology and the academic thought in TCM.

Background: Visceral white adipose tissue (vWAT) inflammation is a critical pathology of obesity-caused heart damage and is closely associated with adipocyte endoplasmic reticulum (ER) dysfunction. Serine (or cysteine) peptidase inhibitor, clade A, member 3C (Serpina3c) has been identified as an adipokine with anti-vWAT inflammatory effects. However, it remains unclear whether Serpina3c deficiency promotion of vWAT inflammation involves adipocyte ER dysfunction and whether it further contributes to heart damage in obesity. Methods: Wild type and Serpina3c knockout (Serpina3c–/–) mice were fed a high-fat diet (HFD) for 12 weeks. An adeno-associated virus (AAV) was injected locally into epididymal white adipose tissue (eWAT) of Serpina3c–/– mice to induce eWAT-adipocyte- specific overexpression of Serpina3c (AAV-Serpina3c) or knockdown of hypoxia-inducible factor 1α (AAV-shHIF1α). In vitro experiments were performed in 3T3-L1 adipocytes. Results: Serpina3c–/– mice exhibited more severe eWAT, serum and heart inflammation after HFD feeding. Consistently, these adverse phenotypes were mitigated in AAV-Serpina3c and AAV-shHIF1α mice. Mechanistically, ER oxidoreductase 1α (Ero1α) and protein disulfide isomerase (PDI) family members PDIA3 and PDIA4 were found to be target genes of HIF1α. In the obese mice, Serpina3c deficiency caused adipocyte more hypertrophy, and activated HIF1α-Ero1α/PDI mediated ER overoxidation and ER stress in eWAT. Subsequently, this led to increased adipocyte apoptosis and chemokine production and decreased adiponectin expression, which promoted macrophage infiltration and M1 polarization in eWAT, thus exacerbating eWAT inflammation and ultimately facilitating serum and distal heart inflammation. Conclusion These findings indicate that Serpina3c is a significant regulator of adipocyte ER redox homeostasis, thus highlighting Serpina3c as a potential therapeutic target for obesity-related eWAT inflammation and heart damage.

Objective To summarize the clinical characteristics and analyze prognostic factors of neuroblastoma (NB) in infants (≤12 months) at a single center. Methods A retrospective analysis was conducted on the clinical data of infant patients (≤12 months) diagnosed with NB and treated between January 2014 and December 2022. Clinical features were analyzed, and comparisons between two sample rates were performed using the χ² test. Univariate prognostic analysis was conducted using the log-rank test, and survival outcomes were analyzed using the Kaplan-Meier method. Results A total of 42 infants (≤12 months) with NB were enrolled. Low-risk patients underwent surgical resection alone; intermediate-risk patients received surgery combined with chemotherapy with or without maintenance therapy; high-risk patients were treated with surgery and chemotherapy with or without maintenance therapy or radiotherapy. The 5-year event-free survival (EFS) rate was (92.7±4.9)%, and the 5-year overall survival rate was (95.2±3.6)%. Only two patients died because of tumor recurrence or progression. Univariate analysis identified MYCN amplification and the initial lactate dehydrogenase (LDH) level ≥ five times the upper limit of the normal were significantly associated with poor prognosis (5-year EFS: 33.3% vs. 97.4% and 60.0% vs. 97.3%, P<0.0001 and P=0.0035). Conclusion Infant NB has a favorable overall prognosis. MYCN amplification and markedly elevated initial LDH are associated with poor outcomes.

Objective:To evaluate the relationship between NAD + -dependent protein deacylase sirtuin-1 (SIRT1) and tau protein during cardiopulmonary bypass (CPB)-induced neuroinflammation in rats. Method:Thirty-six healthy adult male Sprague-Dawley rats, weighing 250-300 g, were used in this study. Eighteen rats were divided into 3 groups ( n=6 each) using a random number table method: sham operation group (C1 group), CPB1 group and tau protein inhibitor methionine+ CPB group (methionine+ CPB group). Another 18 rats were divided into 3 groups ( n=6 each) using a random number table method: sham operation group (C2 group), CPB2 group and SIRT1 agonist SRT1720+ CPB group (SRT+ CPB group). Methionine+ CPB group received oral methionine 10.5 mg/kg once a day for 7 consecutive days. SRT1720 10 mg/kg was intraperitoneally injected once a day for 5 consecutive days in SRT+ CPB group. The model of CPB was developed after the end of drug administration. Rats were weaned off the bypass system after 1 h of circulatory support and sacrificed, and brain tissues were harvested for determination of the contents of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-4 (using enzyme-linked immunosorbent assay), expression of CD32, ARG1, SIRT1, tau protein and acetylated tau protein (ac-tau) (by Western blot), and expression of CD32, ARG1, SIRT1 and tau mRNA (by quantitative real-time polymerase chain reaction). Results:Compared with C1 group, the contents of TNF-α and IL-6 were significantly increased, the content of IL-4 was decreased, the expression of tau and CD32 protein and mRNA was up-regulated, and the expression of ARG1 protein and mRNA was down-regulated in CPB1 group ( P<0.05). Compared with CPB1 group, the contents of TNF-α and IL-6 were significantly decreased, the content of IL-4 was increased, the expression of tau and CD32 protein and mRNA was down-regulated, and the expression of ARG1 protein and mRNA was up-regulated in M+ CPB group ( P<0.05). Compared with C2 group, the contents of TNF-α and IL-6 were significantly increased, the content of IL-4 was decreased, the expression of ac-tau and tau and CD32 protein and mRNA was up-regulated, and the expression of SITR1 and ARG1 protein and mRNA was down-regulated in CPB2 group ( P<0.05). Compared with CPB2 group, the contents of TNF-α and IL-6 were significantly decreased, the content of IL-4 was increased, the expression of ac-tau and tau and CD32 protein and mRNA was down-regulated, and the expression of SITR1 and ARG1 protein and mRNA was up-regulated in SRT+ CPB group ( P<0.05). Conclusions:The down-regulated SIRT1 expression in brain tissues after cardiopulmonary bypass can inhibit deacetylation of tau protein, promote M1 polarization of microglia, inhibit M2 polarization, and ultimately induce neuroinflammation in rats.

Objective:To evaluate the diagnostic value of the vesical imaging-reporting and data system（VI-RADS）for determining muscle invasion in variant histology urothelial carcinoma（VUC）of the bladder.Methods:A retrospective analysis was performed on the pathological and imaging data of 518 bladder cancer patients admitted to Jiangsu Province Hospital between January 2013 and January 2023. Patients were stratified into pure urothelial carcinoma（PUC）group（ n = 457）and variant urothelial carcinoma（VUC）group（ n = 61）based on the presence of histological variants. In the PUC group，there were 390 males（85.3%）and 67 females（14.7%），with a mean age of（66.9 ± 11.2）years. Tumor characteristics included maximum diameter ≥ 30 mm in 149（32.6%），< 30 mm in 308（67.4%），multiple tumors in 147（32.2%），solitary in 310（67.8%），pedunculated morphology in 143（31.3%）and non-pedunculated in 314（68.7%）. Histological grading identified high-grade tumors in 319 patients（69.8%）and low-grade tumors in 138（30.2%）. Pathological stage distribution included 191 of T a（41.8%），127 of T 1（27.8%），76 of T 2（16.6%），47 of T 3（10.3%），and 16 of T 4（3.5%）patients. The VUC group included 61 patients，comprising 51 males（83.6%）and 10 females（16.4%），with a mean age of（65.8 ± 11.4）years. Tumor characteristics were maximum diameter ≥ 30 mm in 38（62.3%），< 30 mm in 23（37.7%），multiple tumors in 16（26.2%），solitary in 45（73.8%），pedunculated morphology in 11（18.0%）and non-pedunculated in 50（82.0%）. Histological grading identified high-grade tumors in 59 patients（96.7%）and low-grade tumors in 2（3.3%）. Pathological stage distribution included 3 of T a（4.9%），15 of T 1（24.6%），15 of T 2（24.6%），20 of T 3（32.8%），and 8 of T 4（13.1%）patients. No statistically significant differences were found between the two groups in gender，age，or tumor multiplicity（ P > 0.05）. Statistically significant differences were found in pathological grade，pathological stage，maximum tumor diameter，and pedunculated morphology（ P < 0.05）. Furthermore，an external validation cohort of 278 bladder cancer patients treated between February 2023 and February 2024 from multiple centers（Jiangsu Provincial People’s Hospital，The First Affiliated Hospital of Zhengzhou University，Union Hospital Tongji Medical College Huazhong University of Science and Technology，Jiangsu Provincial Hospital of Traditional Chinese Medicine，Suzhou Municipal Hospital，Huaian First People’s Hospital，Yixing People’s Hospital）was retrospectively analyzed to externally validate the performance of VI-RADS scoring in predicting muscle invasion of VUC. This cohort included a PUC subgroup of 241 patients，comprising 196 males（81.3%）and 45 females（18.7%），with a mean age of（68.0 ± 10.7）years. Tumor characteristics were maximum diameter ≥ 30 mm in 85（35.3%），< 30 mm in 156（64.7%），multiple tumors in 65（27.0%），solitary in 176（73.0%），pedunculated morphology in 76（31.5%）and non-pedunculated in 165（68.5%）. Histological grading identified high-grade tumors in 175 patients（72.6%）and low-grade tumors in 66（27.4%）. Pathological staging comprised 107 patients of T a（44.4%），78 of T 1（32.4%），22 of T 2（9.1%），22 of T 3（9.1%），and 12 of T 4（5.0%）. The VUC subgroup consisted of 37 patients，comprising 29 males（78.4%）and 8 females（21.6%），with a mean age of（70.5 ± 9.5）years. Tumor characteristics were maximum diameter ≥ 30 mm in 23（62.2%），< 30 mm in 14（37.8%），multiple tumors in 9（24.3%），solitary in 28（75.7%），pedunculated morphology in 7（18.9%）and non-pedunculated in 30（81.1%）. Histological grading identified high-grade tumors in 36 patients（97.3%）and low-grade tumors in 1（2.7%）. Pathological staging comprised 1 patient of T a（2.7%），9 of T 1（24.3%），7 of T 2（18.9%），19 of T 3（51.4%），and 1 of T 4（2.7%）. In this validation cohort，no significant differences were found in gender，age，tumor multiplicity，or pedunculated morphology between the PUC and VUC subgroups（ P > 0.05）. Significant differences were observed in pathological grade，pathological stage，and maximum tumor diameter（ P < 0.05）. Three radiologists independently reviewed and scored the multiparametric MRI（mp-MRI）in a blinded manner. Inter-reader agreement was assessed using the weighted kappa statistic. Differences in variables between the two groups were compared using t-tests，chi-square tests，or Fisher’s exact test. The diagnostic performance of VI-RADS for muscle invasion in VUC and PUC was comprehensively evaluated using receiver operating characteristic（ROC）curves，the area under the curve（AUC），and cut-off values determined by the Youden’s index. The DeLong test was used to assess whether the diagnostic performance of VI-RADS differed between VUC and PUC. Results:In the retrospective single-center cohort，the AUC of VI-RADS for assessing muscle invasion was 0.895（95% CI 0.864?0.922）in the PUC group，with a cut-off value of > 3，and the AUC was 0.896（95% CI 0.791-0.960）in the VUC group，with a cut-off value of > 3. The difference between the two groups was not statistically significant（ P = 0.986）. Using a VI-RADS score > 3 as the cut-off value，the accuracy，sensitivity，specificity，positive predictive value（PPV），and negative predictive value（NPV）for diagnosing muscle invasion status in the PUC group were 85.8%（392/457），70.5%（98/139），92.5%（294/318），80.3%（98/122），and 87.8%（294/335），respectively. The corresponding values for the VUC group were 82.0%（50/61），76.7%（33/43），94.4%（17/18），97.1%（33/34），and 63.0%（17/27）.In the retrospective multicenter cohort，the AUC of VI-RADS for assessing muscle invasion was 0.891（95% CI 0.845?0.927）in the PUC group，with a cut-off value of > 2，and the AUC was 0.898（95% CI 0.754?0.973）in the VUC group，with a cut-off value of > 3. The difference between the two groups was not statistically significant（ P = 0.897）. Using a VI-RADS score > 3 as the cut-off value，the accuracy，sensitivity，specificity，PPV，and NPV for diagnosing muscle invasion status in the PUC group were 85.9%（207/241），58.9%（33/56），94.1%（174/185），75.0%（33/44），and 88.3%（174/197），respectively. The corresponding values for the VUC group were 81.1%（30/37），77.8%（21/27），90.0%（9/10），95.5%（21/22），and 60.0%（9/15）.In the single-center cohort，the Kappa values for inter-reader agreement in assessing muscle invasion status using VI-RADS were 0.881（ P < 0.01）for the PUC group and 0.941（ P < 0.01）for the VUC group among the three readers. In the multicenter cohort，the Kappa values were 0.858（ P < 0.01）for the PUC group and 0.838（ P < 0.01）for the VUC group. Conclusions:VI-RADS demonstrates similarly high diagnostic performance for assessing muscle invasion in both PUC and VUC，which is applicable for diagnosing muscle invasion status in VUC，and shows good inter-reader agreement.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.