Background: The cause of aggravation of diabetic myocardial damage is yet to be elucidated; damage to mitochondrial function has been a longstanding focus of research. During diabetic myocardial ischaemia–reperfusion (MI/R), it remains unclear whether reduced mitochondrial fusion exacerbates myocardial injury by generating free damaged mitochondrial DNA (mitoDNA) and activating the cGAS-STING pathway.Methods: In this study, a mouse model of diabetes was established (by feeding mice a high-fat diet (HFD) plus a low dose of streptozotocin (STZ)), a MI/R model was established by cardiac ischaemia for 2 h and reperfusion for 30 min, and a cellular model of glycolipid toxicity induced by high glucose (HG) and palmitic acid (PA) was established in H9C2 cells.Results: We observed that altered mitochondrial dynamics during diabetic MI/R led to increased mitoDNA in the cytosol, activation of the cGAS-STING pathway, and phosphorylation of the downstream targets TBK1 and IRF3. In the cellular model we found that cytosolic mitoDNA was the result of reduced mitochondrial fusion induced by HG and PA, which also resulted in cGAS-STING signalling and activation of downstream targets. Moreover, inhibition of STING by H-151 significantly ameliorated myocardial injury induced by MFN2 knockdown in both the cell and mouse models. The use of a fat-soluble antioxidant CoQ10 improved cardiac function in the mouse models.Conclusions: Our study elucidated the critical role of cGAS-STING activation, triggered by increased cytosolic mitoDNA due to decreased mitochondrial fusion, in the pathogenesis of diabetic MI/R injury. This provides preclinical insights for the treatment of diabetic MI/R injury.Graphical

Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal cell carcinoma, acute kidney injury, renal fibrosis, diabetic nephropathy, and lupus nephritis. However, the role of epigenetic regulation in calcium oxalate (CaOx) crystal deposition-induced kidney injury remains unclear. Our study demonstrated that the upregulation of enhancer of zeste homolog 2 (EZH2)-mediated ferroptosis facilitates CaOx-induced kidney injury. CaOx crystal deposition promoted ferroptosis in vivo and in vitro. Usage of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, mitigated CaOx-induced kidney damage. Single-nucleus RNA-sequencing, RNA-sequencing, immunohistochemical and western blotting analyses revealed that EZH2 was upregulated in kidney stone patients, kidney stone mice, and oxalate-stimulated HK-2 cells. Experiments involving in vivo EZH2 knockout, in vitro EZH2 knockdown, and in vivo GSK-126 (an EZH2 inhibitor) treatment confirmed the protective effects of EZH2 inhibition on kidney injury and ferroptosis. Mechanistically, the results of RNA-sequencing and chromatin immunoprecipitation assays demonstrated that EZH2 regulates ferroptosis by suppressing solute carrier family 7, member 11 (SLC7A11) expression through trimethylation of histone H3 lysine 27 (H3K27me3) modification. Additionally, SOX4 regulated ferroptosis by directly modulating EZH2 expression. Thus, this study demonstrated that SOX4 facilitates ferroptosis in CaOx-induced kidney injury through EZH2/H3K27me3-mediated suppression of SLC7A11. Graphical Abstract

Chronic kidney disease (CKD) is a major global health concern. Renal fibrosis, a prevalent outcome regardless of the initial cause, ultimately leads to end-stage renal disease. Glomerulosclerosis and renal interstitial fibrosis are the primary pathological features. Preventing and slowing renal fibrosis are considered effective strategies for delaying CKD progression. However, effective treatments are lacking. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase belonging to class III histone deacetylases, is implicated in the physiological regulation and protection of the kidney and is susceptible to a diverse array of pathological influences, as demonstrated in previous studies. Interestingly, controversial conclusions have emerged as research has progressed. This review provides a comprehensive summary of the current understanding and advancements in the field; specifically, the biological roles and mechanisms of SIRT1 in regulating renal fibrosis progression. These include aspects such as lipid metabolism, epithelial-mesenchymal transition, oxidative stress, aging, inflammation, and autophagy. This manuscript explores the potential of SIRT1 as a therapeutic target for renal fibrosis and offers new perspectives on treatment approaches and prognostic assessments.

Diabetic nephropathy, a common and severe complication of diabetes, is the leading cause of end-stage renal disease, ultimately leading to renal failure and significantly affecting the prognosis and lives of diabetics worldwide. However, the complexity of its developmental mechanisms makes treating diabetic nephropathy a challenging task, necessitating the search for improved therapeutic targets. Intercellular communication underlies the direct and indirect influence and interaction among various cells within a tissue. Recently, studies have shown that beyond traditional communication methods, tunnel nanotubes, exosomes, filopodial tip vesicles, and the fibrogenic niche can influence pathophysiological changes in diabetic nephropathy by disrupting intercellular communication. Therefore, this paper aims to review the varied roles of intercellular communication in diabetic nephropathy, focusing on recent advances in this area.

Cancers of the urinary system account for 13.1% of new cancer cases and 7.9% of cancer-related deaths. Of them, renal cancer, bladder cancer, and prostate cancer are most prevalent and pose a substantial threat to human health and the quality of life. Prostate cancer is the most common malignant tumor in the male urinary system. It is the second most common type of malignant tumor in men, with lung cancer surpassing its incidence and mortality. Bladder cancer has one of the highest incidences and is sex-related, with men reporting a significantly higher incidence than women. Tumor development in the urinary system is associated with factors, such as smoking, obesity, high blood pressure, diet, occupational exposure, and genetics. The treatment strategies primarily involve surgery, radiation therapy, and chemotherapy. Cholesterol metabolism is a crucial physiological process associated with developing and progressing urinary system tumors. High cholesterol levels are closely associated with tumor occurrence, invasion, and metastasis. This warrants thoroughly investigating the role of cholesterol metabolism in urinary system tumors and identifying novel treatment methods for the prevention, early diagnosis, targeted treatment, and drug resistance of urinary system tumors.