Journal of Steroid Biochemistry and Molecular Biology最新文献

{"title":"Drug repurposing opportunities for breast cancer and seven common subtypes.","authors":"Yilong Lin, Songsong Wang, Yun Zhang, Jing She, Yue Zhang, Ruidan Zhao, Zhongquan Qi, Ruiqin Yang, Liyi Zhang, Qingmo Yang","doi":"10.1016/j.jsbmb.2024.106652","DOIUrl":"10.1016/j.jsbmb.2024.106652","url":null,"abstract":"<p><p>Breast cancer is a substantial global health problem, and drug repurposing provides novel opportunities to address the urgent need for therapeutics. According to significant Mendelian randomization (MR) results, we identified 26 genes for overall breast cancer, 25 genes for ER+ breast cancer and 4 genes (CASP8, KCNN4, MYLK4, TNNT3) for ER- breast cancer. In order to explore the differences between 5 intrinsic subtypes, we found 29 actionable druggable genes for Luminal A breast cancer, 2 genes (IGF2 and TNNT3) for Luminal B breast cancer, 1 gene (FAAH) for Luminal B HER2 negative breast cancer, and 3 genes (CASP8, KCNN4, and TP53) for triple-negative breast cancer. After colocalization analysis, we determined OPRL1 as a prioritized target in both overall and Luminal A breast cancer. Additionally, FES and FAAH were considered prioritized targets for ER+ breast cancer. Through molecular docking, crizotinib stand out as a prioritized FES target drug repurposing opportunity with the lowest binding energy (-10.13 kJ·mol^-1) and CCK-8 assay showed ER+ cell groups were more sensitive to crizotinib than ER- cell groups. In conclusion, OPRL1 was identified as a prioritized target for both overall and Luminal A breast cancer. Moreover, FES and FAAH were recognized as prioritized targets for ER+ breast cancer.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106652"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CaCo-2 cell junction derangement exerted by the single addition of oxysterols commonly detected in foods is markedly quenched when they are in mixture.","authors":"Noemi Iaia, Federico Canzoneri, Fiorella Biasi, Giuseppe Poli, Roberto Menta, Gabriella Testa, Paola Gamba","doi":"10.1016/j.jsbmb.2024.106648","DOIUrl":"10.1016/j.jsbmb.2024.106648","url":null,"abstract":"<p><p>The selective permeability of the gut epithelial barrier is heavily reliant on the stability of cell junctions, often challenged by a variety of dietary stressors, including non-enzymatic cholesterol oxidation products (COPs). A marked decrease of the tight junctions claudin-1 and occludin, and of the adherens junction E-cadherin was previously detected in differentiated CaCo-2 monolayers challenged by a single addition of 7β-hydroxycholesterol (7βOHC) or 7-ketocholesterol (7KC) in the lowest micromolar range. However, in the diet, oxysterols are occurring in a mixture. Hence, the aim of the present study was to evaluate whether cell incubation with all the main dietary COPs together quench the intercellular junction derangement previously observed as exerted by 7βOHC and 7KC singularly added. Two chocolate prototypes, respectively made with fresh (oxy-Mix1) or six-months stored whole milk powder (oxy-Mix2), were compared. The second prototype showed an almost double content of total COPs (3.34 µM, approximately 1337 ng /g of chocolate) than the first one (1.69 µM, approximately 675 ng /g of chocolate). Importantly, even in the CaCo-2 cell monolayers treated with six-months stored mixture of COPs oxy-Mix2, no alterations were observed of those cell junctions markedly affected by identical concentration of 7βOHC or 7KC used alone. The junctions' derangement started to be significantly evident when oxy-Mix2 was used at higher concentration (5 µM, approximately 2 µg oxysterols/g of product) or when treatments were carried out with repeated doses of oxy-Mix2 every 24 hours. Although achieved in a still widely adopted in vitro model system, these findings could orientate the definition of a safe shelf-life for dairy products, certainly for milk chocolate.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106648"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The determination of endogenous steroids in hair and fur: A systematic review of methodologies.","authors":"Padraig Maher, Martin Healy, Eamon Laird, Jelena Marunica Karšaj, Wei Gao, Lina Zgaga","doi":"10.1016/j.jsbmb.2024.106649","DOIUrl":"10.1016/j.jsbmb.2024.106649","url":null,"abstract":"<p><strong>Background: </strong>Endogenous steroid hormone assessment is essential for clinical practice. These hormones are typically measured in blood. More recently, measurement of steroids in hair samples has been gaining in popularity, so we have reviewed the methodologies used for this to-date.</p><p><strong>Methods: </strong>Ovid Medline, CINAHL, Psychinfo, and EMBASE were searched to identify manuscripts that analysed cortisol, testosterone, androstenedione, 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone sulphate (DHEAS), and/or 25-hydroxyvitamin D (25(OH)D), in hair or fur. Data related to sampling and measurement procedures were extracted and analysed.</p><p><strong>Results: </strong>The systematic review included a total of 180 papers, with 82 % published in the past 8 years; 67 % were human and 33 % animal studies. Cortisol was by far the most common analyte. Incomplete reporting on sample harvest, preparation, and measurement procedures was common. Typically, samples were collected from posterior vertex of humans or back/neck of animals, weighing between 11 and 50 mg (with a range of 1.25-1000 mg). Samples were usually stored at room temperature, often using aluminium foil. Isopropanol was the most common cleaning solution. Hair was normally powdered or segmented prior to extraction. Extraction was typically carried out over 18-24 hours using methanol. Validation and precision information was provided in 47 % of studies.</p><p><strong>Conclusions: </strong>This systematic review highlights the lack of standardisation in the analysis of endogenous steroids in hair. Reporting was typically incomplete, and assay validations were partial or absent. Together, these limit the value of these exciting new methods and hold back transition to clinical use.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106649"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low progesterone levels and their role in the co-existence of polycystic ovary syndrome and rheumatoid arthritis: a comprehensive analysis among Iraqi patient.","authors":"Mohammed Mahdi Sami, Mataz J Jamai, Tamara Ahmed Abd Alkareem, Nabeel Bunyan Ayram","doi":"10.1016/j.jsbmb.2025.106680","DOIUrl":"https://doi.org/10.1016/j.jsbmb.2025.106680","url":null,"abstract":"<p><p>Polycystic ovarian syndrome (PCOS) is a low-grade and chronic inflammation defined by irregular hormonal status that primarily triggers females in their reproductive age. Multi cysts are a primary manifestation of PCOS; a high level of androgen production characterizes the condition via ovaries. Rheumatoid arthritis (RA) is a chronic, systemic, and symmetrical inflammatory autoimmune disease that affects 1-2% of adults. Females are more likely to generate RA. During the inflammatory activity, immune cells attack the synovium and the synovial space. This invasion is essential in releasing many cytokines in the synovial and joint spaces, leading to joint damage and pain, stiffens, heat, and tenderness in the joint. To evaluate the strength of the link between PCOS and RA, the cross-sectional study examined hormonal, metabolic, and autoantibodies in PCOS, RA as a positive control and the study groups. Statistical analysis Shapiro-Wilk test, student t-test, one-way ANOVA, and multi-linear regression analysis were used to evaluate the results. The data highlights significant values for the BMI, WHR, and hirsutism of PCOS and RA groups in comparison to the negative control. The ANOVA results of these parameters also showed a significant p<0.05 among the groups. According to the negative control, the levels of insulin, HOMA-IR, testosterone, LH, estradiol, and CRP showed a substantial increase in the PCOS group. Also, the RA group showed a significant p<0.05 rise in CRP, RF, and Ani-CCP, and the ANOVA results showed significant value among the groups under investigation. Progesterone D as a model showed a correlation with Anti-CCP B, RF C, Anti-CCP C, CRP D, RF D, and Anti-CCP D with the highest level of f² between other models. In addition, statistical tests show that progesterone D with R²=0.565 and RMSE equal to 0.996 have heteroscedasticity, which means that low levels of progesterone are associated inversely with high levels of RF and Anit-CCP. There is a relative association between the progesterone D model and corresponding predictions. Regardless of solid f², only 56% of the sample shows an association between the model and predictors; this relation may differ if we consider the study's limitations.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106680"},"PeriodicalIF":2.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signaling crosstalk of Galectin-3, β-catenin, and estrogen receptor in androgen-independent prostate cancer DU-145 cells.","authors":"Deborah Simão Souza, Carolina Meloni Vicente, Carla Macheroni, Vanessa Leiria Campo, Catarina Segreti Porto","doi":"10.1016/j.jsbmb.2025.106679","DOIUrl":"10.1016/j.jsbmb.2025.106679","url":null,"abstract":"<p><p>The aims of this study were to investigate the localization of non-phosphorylated β‑catenin and Galectin-3 (GAL-3), the regulation of the expression of both proteins by activation of estrogen receptors (ERs) and their role in tumorigenic characteristics of androgen-independent prostate cancer DU-145 cells. DU-145 cells were cultured in the absence (control), and presence of 17β-estradiol (E2). Cells were also untreated or pre-treated with the inhibitor of GAL‑3, VA03, or with a compound that disrupts the complex β-catenin-TCF/LEF transcription factor, PKF 118-310. Immunofluorescence assay for non-phosphorylated β-catenin and GAL-3, cell proliferation, wound healing and cell invasion assays were performed. 17β-estradiol (E2, 4 h) increased the expression of non-phosphorylated β-catenin and GAL-3. E2 also increased (2-fold) the co-localization of the fluorescence of non-phosphorylated β-catenin and GAL‑3 in the whole cells compared to the control. The up-regulation of non-phosphorylated β-catenin expression was blocked by VA03, suggesting that GAL-3 is upstream protein involved in this process. E2 (24 h) increased the cell number, migration, and invasion of the DU‑145 cells compared to control. Furthermore, PKF 118-310 completely blocked the proliferation, migration, and invasion of the DU-145 cells induced by activation of ERs. The activation of ERs increases the expression, co-localization and signaling of the GAL-3 and non-phosphorylated β-catenin in DU-145 cells. Non-phosphorylated β-catenin is downstream protein involved in proliferation, migration, and invasion of the DU‑145 cells.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106679"},"PeriodicalIF":2.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The double disparity: Vitamin D deficiency and lethal prostate cancer in black men.","authors":"Adriana Duraki, Kirsten D Krieger, Larisa Nonn","doi":"10.1016/j.jsbmb.2025.106675","DOIUrl":"10.1016/j.jsbmb.2025.106675","url":null,"abstract":"<p><p>Epidemiological data from as early as the 1930s documented a dramatic racial disparity in prostate cancer incidence, survival, and mortality rates among Black men-a trend that persists to this day. Black men are disproportionately burdened by prostate cancer, developing the disease at younger ages, facing more aggressive and lethal forms, and ultimately experiencing double the mortality rate of men of European descent. Investigating the multifactorial contributors to this racial disparity has been extensive, but results have often been inconsistent or inconclusive, making it difficult to pinpoint clear correlations. However, there is strong evidence suggesting that vitamin D deficiency is significantly associated with lethal forms of prostate cancer. This is particularly important given that Black men are at a higher risk for both vitamin D deficiency and developing aggressive, lethal prostate cancer, presenting a double disparity. The disparity in prostate cancer and vitamin D extends to Black men outside the US, but most of the studies have been done in African American men. Understanding the available evidence on vitamin D deficiency and its influence on prostate cancer biology may reveal new opportunities for prevention and therapeutic intervention.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106675"},"PeriodicalIF":2.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between serum 25-hydroxyvitamin D concentrations and urinary vitamin D metabolite concentrations measured by the NLucVDR assay.","authors":"Takuya Kushioka, Hiroki Mano, Sayuri Matsuoka, Miyu Nishikawa, Kaori Yasuda, Shinichi Ikushiro, Toshiyuki Sakaki","doi":"10.1016/j.jsbmb.2025.106678","DOIUrl":"https://doi.org/10.1016/j.jsbmb.2025.106678","url":null,"abstract":"<p><p>It is well known that vitamin D is essential for human health; however, many people suffer from vitamin D deficiency or insufficiency worldwide, including in Japan. Serum 25-hydroxyvitamin D (25(OH)D) concentrations are typically measured to evaluate vitamin D status. In a previous study, we demonstrated that the concentrations of vitamin D metabolites in urine, measured using the NLucVDR assay system composed of a split-type nanoluciferase and the ligand-binding domain (LBD) of the human vitamin D receptor, correlated with serum 25(OH)D concentrations measured using liquid chromatography-mass spectrometry (LC-MS) or electrochemiluminescence immunoassays (ECLIAs). However, the number of participants was limited to 23. In the present study, we investigated the relationship between urinary vitamin D metabolite concentrations measured using the NLucVDR assay and serum 25(OH)D concentrations measured using ECLIA in 292 healthy individuals aged 20-69 years. We observed a significant positive correlation between 25(OH)D concentrations and urinary vitamin D metabolite concentrations (r = 0.400, p <0.001). Furthermore, in a multiple regression model with serum 25(OH)D concentrations as the dependent variable and urinary vitamin D metabolite concentrations, sex, age, body mass index (BMI), and vitamin D intake as independent variables, urinary vitamin D metabolite concentrations showed a significant positive association with serum 25(OH)D concentrations regardless of sex, age, BMI, and vitamin D intake. Additionally, receiver operating characteristic (ROC) curve analysis was performed to evaluate whether this multiple regression model could predict vitamin D deficiency. The area under the curve (AUC) was 0.743 and 0.708 for women and men with vitamin D deficiency (serum 25(OH)D < 20ng/mL), respectively. Our results suggest that urinary vitamin D metabolite concentrations, measured by the NLucVDR assay, may be useful for the noninvasive predictive tool of vitamin D deficiency.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106678"},"PeriodicalIF":2.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the causal effect of genetically predicted metabolites and metabolic pathways on vitiligo: Evidence from Mendelian randomization and animal experiments.","authors":"Guanglu Li, Baoquan Qu, Tao Zheng, Yi Cheng, Ping Li, Zunjing Liu, Jingxia Zhao","doi":"10.1016/j.jsbmb.2025.106677","DOIUrl":"https://doi.org/10.1016/j.jsbmb.2025.106677","url":null,"abstract":"<p><p>Vitiligo is a common chronic skin depigmentation disorder that seriously decreases the patients' overall quality of life. Human blood metabolites could contribute to unraveling the underlying biological mechanisms of vitiligo. We used GWAS summary statistics to assess the causal association between genetically predicted 1400 serum metabolites and vitiligo risk by Mendelian randomization (MR). Then, after constructing the mouse model of vitiligo, we did non-targeted metabolomics analysis on the mouse serum and validated MR's pathway enrichment results ulteriorly. In the initial phase, MR analysis revealed causative associations between 36 metabolites and vitiligo risk, including 8 metabolite ratios and 28 individual metabolites (19 known and 9 unknown metabolites). In the validation stage, 7 metabolites were successfully validated. Of the 28 individual metabolites, most are related to lipid metabolism. Genetically predicted higher 4-oxo-retinoic acid showed the strongest protective effect on vitiligo, while the most potent risk effect was the increase in quinate. The metabolites associated with vitiligo risk are mainly enriched in alpha-linolenic acid metabolism, linoleic acid metabolism, arginine biosynthesis and metabolism pathways, validated through the serum metabolomics of vitiligo mouse. By integrating genomics and metabolomics, this study provides new insights into the association between metabolites and vitiligo, highlighting the potential roles of specific metabolites in the pathogenesis of vitiligo. These metabolites associated with vitiligo could serve as new biomarkers, further research could help to reveal how these metabolites influence specific pathways in the development of vitiligo.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"106677"},"PeriodicalIF":2.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute hyperglycemia induces podocyte apoptosis by monocyte TNF-α release, a process attenuated by vitamin D and GLP-1 receptor agonists.","authors":"Rong M Zhang, Jisu Oh, Burton M Wice, Adriana Dusso, Carlos Bernal-Mizrachi","doi":"10.1016/j.jsbmb.2025.106676","DOIUrl":"10.1016/j.jsbmb.2025.106676","url":null,"abstract":"<p><p>Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that AH (16.7 mM D- glucose) didn't induce podocyte apoptosis directly, but it did promote a pro-inflammatory response in human monocytes and macrophages, resulting in an increased TNF-α secretion causing podocyte apoptosis. The AH-induced monocyte TNF-α secretion was inversely correlated with healthy donors' serum 25(OH)D levels. AH induced monocyte TNF-α release by increasing oxidative and ER stress, which in turn increased ADAM17 (A Disintegrin And Metalloprotease 17) and iRhom2 (inactive Rhomboid protein 2) expression, both essential for TNF-α secretion. Additionally, monocyte activation of glucagon-like peptide-1 receptor (GLP-1R), using a GLP-1R agonist, downregulated ADAM17/iRhom2 expression, decreasing TNF-α release and reducing podocyte apoptosis. These results show that a normal vitamin D status may attenuate a mechanism by which AH contributes to podocyte apoptosis and CKD progression and might enhance a novel anti-inflammatory role of GLP-1 to prevent AH-driven CKD progression in diabetes.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106676"},"PeriodicalIF":2.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of DDB2 in type II diabetes mellitus induces dysregulated ubiquitination of KMT2A in lipid metabolism disorders.","authors":"Lvqiu Li, Maogeng Yang, Longqiao Tan, Yanhong Ni, Yang Wu","doi":"10.1016/j.jsbmb.2025.106673","DOIUrl":"10.1016/j.jsbmb.2025.106673","url":null,"abstract":"<p><p>The disorders of glucose and lipid metabolism contribute to severe diseases, including cardiovascular disease, diabetes, and fatty liver. Here, we identified DNA damage-binding protein 2 (DDB2), an E3 ubiquitin ligase, as a pivotal regulator of lipid metabolism disorders in type II diabetes mellitus (T2DM). A mouse model of T2DM and primary mouse hepatocytes with steatosis were induced. DDB2 overexpression alone or in combination with lysine N-methyltransferase 2 A (KMT2A) overexpression vectors were delivered into db/db mice and in vitro hepatocytes. DDB2 was expressed poorly, while KMT2A was expressed highly in liver tissues and primary hepatocytes of db/db mice. DDB2 ameliorated glucose intolerance and insulin resistance, decreased liver/body weight ratio, downregulated expression of lipogenesis-associated proteins (SREBP1, FASN, and SCD1) and gluconeogenesis-related proteins (PEPCK and G6Pase) in liver tissues and cells, and decreased triglyceride and total cholesterol levels in steatotic hepatocytes. DDB2 reduced KMT2A expression through ubiquitination modification. Overexpression of KMT2A promoted insulin resistance, lipogenesis and lipid deposition, and glycogen accumulation in the presence of DDB2. Overall, our data demonstrate that DDB2 alleviates hepatic lipogenesis and lipid deposition via degradation of KMT2A, thereby repressing lipid metabolism disorders in T2DM.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106673"},"PeriodicalIF":2.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}