Mitochondrial function is a central determinant of cardiomyocyte survival, yet mitochondrial pharmacology remains under-integrated into cardiovascular and antidiabetic drug classification, safety assessment, and therapeutic decision-making. Many cardiometabolic drugs exert direct or indirect effects on mitochondrial bioenergetics, redox balance, calcium handling, quality control, and genome stability effects that can confer protection in some contexts while precipitating toxicity in others. In diseased myocardium, where mitochondrial reserve is constrained by ischemia, metabolic stress, ageing, or heart failure, these drug-mitochondria interactions frequently dictate clinical benefit or harm beyond the nominal drug class.This review synthesises the mitochondrial actions of widely used cardiovascular and antidiabetic therapies, including statins, renin-angiotensin-aldosterone system inhibitors, β-blockers, metformin, sodium-glucose cotransporter-2 inhibitors, and incretin-based agents, across acute and chronic exposure windows. We integrate key mechanistic domains encompassing electron transport chain modulation, redox and cofactor reprogramming, calcium permeability transition coupling, mitochondrial dynamics, mitophagy, and stress signalling, and relate these signatures to clinically relevant cardiometabolic disease contexts.We propose a unifying framework in which mitochondrial reserve capacity and quality control competence function as the central decision node determining whether pharmacologic mitochondrial engagement is adaptive or injurious. Finally, we outline principles for mitochondria-conscious prescribing, risk stratification, and drug development, and propose that systematic incorporation of mitochondrial endpoints into clinical trials and safety pipelines is essential for advancing precision cardiometabolic therapy.
Background Bone regulates whole-body homeostasis via secretory proteins, and clinical observations have suggested potential links between certain skeletal pathologies and liver abnormalities under specific clinical contexts. Results This study established a postnatal-specific osteocyte knockout mouse model (Dmp1cre DTRfl/fl). Livers were collected for Single-cell RNA sequencing (scRNA-seq), bulk transcriptomic analysis, and metabolomic analysis to reveal the impact of osteocytes ablation on liver metabolism. Multi-omics analysis revealed alterations in lipid metabolism, with upregulation of Cyp4a10 related to oxidative stress and lipid peroxidation, and downregulation of Scd1 involved in fatty acid biosynthesis. scRNA-seq identified changes in gene expression patterns in hepatocytes, endothelial cells, and Kupffer cells, with key transcription factors (Yy1 in hepatocytes and Etv5 in endothelial cells) associated with steatosis. Altered cellular communication networks, particularly the Grn-sort1 and Angptl4-Sdc axes, potentially reshaped liver metabolism and facilitated steatosis in Dmp1cre DTRfl/fl mice. Histological analysis confirmed the development of hepatic steatosis in Dmp1cre DTRfl/fl mice. Conclusions Loss of osteocytes has potential role in liver lipid metabolic disturbances and fat accumulation, mediated through the modulation of lipid and inflammatory gene expression and alterations in intra-cellular communication within the liver. These findings enhance our understanding of how bone disease can initiate systemic metabolic disorders and provide support for the concept of the bone-liver axis.
Heart disease in elderly is commonly driven by age-related detriment in cardiac structure and function. Cell adhesion associated, oncogene regulated (CDON) plays an important part in heart remodeling and function. However, the involvement of CDON in cardiac aging remains elusive. Here, we determined age-related alteration of cardiac structure and function as well as gene effects in mouse models and cardiomyocytes. Our results showed that aged mice had decreased CDON expression accompanied by cardiac hypertrophy, fibrosis, declined LVEF and LVFS resembling those found in Cdon+/− mice. Moreover, Cdon+/− mice presented an increased cardiac expression in molecular aging markers, including cyclin dependent kinase inhibitors p21 and p16, advanced glycation end products, phosphorylated histone H2AX (γH2AX), apoptosis, proinflammatory Il6 and Il1b, senescence-associated beta-galactosidase (SA-β-gal) activity and reactive oxygen species (ROS) level. Likewise, knockdown of Cdon in cardiomyocytes elevated senescence marker level. The senescent cardiomyocytes induced by D-galactose exhibited low expression of CDON, while overexpression of Cdon in D-galactose-treated cells attenuated senescence phenotype. Furthermore, forkhead box O3 (FOXO3) was identified as a CDON-downstream target. Cdon knockdown decreased cytoplasmic but increased nuclear FOXO3 expression. Notably, Cdon deficiency reduced AKT serine/threonine kinase 1 (AKT) phosphorylation, leading to nuclear retention of FOXO3, thereby promoting the growth arrest and DNA damage inducible gamma (Gadd45g) transcription. These effects were implicated in the combination of immunoglobulin (1–5) and fibronectin type III (1) domain of CDON. In conclusion, CDON is pivotal in cardiac aging and may modulate cardiomyocyte senescence through AKT/FOXO3/GADD45G cascade.
Background Benign prostatic hyperplasia (BPH), a prevalent disorder among elderly men, still has an unclear etiology. Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) plays a pivotal role in cellular proliferation, differentiation and epithelial-mesenchymal transition (EMT) in various tissues. This study was designed to investigate the roles of LGR4 in BPH. Methods Human prostate tissues, cultured human prostate cell (BPH-1 and WPMY-1) were utilized to detect LGR4 expression and localization by immunofluorescence staining, RT-PCR, and Western Blot. LGR4 deficient and overexpression cell models were established. Using these models, the levels of cellular viability, apoptosis, cell cycle were quantified by cell counting kit-8 assay, flow cytometry, respectively. Apoptosis-related proteins, cycle-associated proteins, EMT biomarkers and Wnt/β-catenin pathway were measured by Western Blot. Furthermore, a software, AlphaFold3, was used to perform molecular docking analysis between LGR4 and RhoA. We further studied the interaction between LGR4 and RhoA through Co-Immunoprecipitation assay. Results Our research findings demonstrated that LGR4 was overexpressed in BPH and localized within the stromal and epithelial components of prostate. LGR4 deficiency promoted apoptosis, arrested the cell cycle, inhibited cell growth and EMT. Conversely, overexpression of LGR4 completely reversed the alterations induced by LGR4 deficiency. We further showed that LGR4 regulated the Wnt/β-catenin pathway by interacting with RhoA to control cellular proliferation, apoptosis and EMT, while barely affected cell cycle. Conclusions Overall, our original data indicate that the upregulated LGR4 could interact with RhoA to exert an inhibitory impact on cell apoptosis while promote cellular proliferation and EMT via Wnt/β-catenin pathway.
Acute myeloid leukemia (AML) is a hematological malignancy characterized by impaired hematopoiesis and aggressive progression, with limited treatment options and poor prognosis, especially in elderly patients. Metabolic reprogramming, particularly enhanced glycolysis, is a hallmark of AML and contributes to disease progression and therapy resistance. Upstream stimulatory factor 1 (USF1) regulates metabolism, the cell cycle, and oncogenesis in solid tumors, whereas its role in AML remains unclear. Herein, we investigated the role and underlying mechanism of USF1 in regulating USP25 transcription and promoting AML progression. We found that USF1 was highly expressed in AML samples and cell lines, and its elevated expression was associated with poor prognosis. Functional assays showed that USF1 promoted AML cell growth and glycolysis while inhibiting apoptosis. Mechanistically, USF1 directly bound to the USP25 promoter, enhancing its transcription. Knockdown of USP25 reversed the tumor-promoting effects of USF1. Moreover, in vivo studies demonstrated that silencing USF1 significantly inhibited tumor growth. In conclusion, USF1 promotes AML cell growth and glycolysis through the transcriptional activation of USP25, thereby identifying the USF1–USP25 axis as a potential therapeutic target for AML.
