Despite optimal glycemic control, the heart failure burden remains substantial in diabetic patients. Metabolic remodeling is involved in this process, yet our current understanding is still in its infancy. Methylmalonic acid (MMA) is conventionally viewed as a marker of cobalamin (Cbl) deficiency. Paradoxically, MMA elevation-related cardiovascular mortality is more pronounced in diabetic patients with normal or high Cbl levels. This study investigated the mechanisms and translational significance of this contradictory MMA accumulation in the diabetic heart.

We analyzed serum Cbl, MMA, and cardiac biomarkers in 12 751 participants and characterized Mmut (methylmalonyl-CoA mutase; a key enzyme in MMA catabolism) expression in failing human hearts with diabetes. Cardiomyocyte-specific Mmut knockout and Mmut-overexpressing mice were subjected to high-fat diet/streptozotocin-induced diabetes. Molecular mechanisms were elucidated using ¹³C-isotope tracing, RNA sequencing, immunoprecipitation, and biolayer interferometry.

Elevated serum MMA was significantly associated with subclinical heart damage and adverse outcomes in diabetic adults, even in the absence of Cbl deficiency. Cardiac MMA overload and decreased protein expression of Mmut were observed in humans and mice with diabetes. Notably, MMA dysmetabolism preceded detectable cardiac dysfunction in diabetic mice and persisted even after glycemic normalization. Mechanistically, the hyperglycemic memory-associated molecule miR-499 binds to Mmut mRNA, suppressing its expression and driving MMA accumulation. Mmut deficiency amplified cardiac MMA overload and exacerbated disturbances in glycolipid metabolism and mitochondrial quality control, whereas adeno-associated virus-mediated Mmut overexpression attenuated cardiac MMA load and adverse remodeling in diabetic mice. Isotope tracing identified isoleucine and valine as the primary sources of cardiac MMA under diabetic conditions. Branched-chain amino acid-restricted diets alleviated diabetes-induced MMA accumulation and heart damage. Crucially, Cbl supplementation failed to alleviate MMA overload in diabetic mice, even at high doses or with activated forms. Strikingly, metformin, an established risk factor for Cbl deficiency, mitigated MMA-induced heart damage through dual mechanisms: activating AMPK (AMP-activated protein kinase)-dependent mitochondrial quality control to enhance tolerance to MMA, and directly promoting Mmut-Cbl cooperation to enhance MMA clearance.

This study provides a foundation for understanding diabetes-related MMA dysmetabolism as a trigger for subclinical heart damage resistant to glycemic control and Cbl supplementation. Our findings challenge the prevailing clinical consensus regarding the impacts of Cbl and metformin use on MMA elevation in diabetic management.

Recent research indicates that the senescence of bone marrow mesenchymal stem cells (BMSCs) disrupts the osteo-adipogenic balance, a primary factor contributing to the development of osteoporosis. Our previous findings have implicated methyltransferases in this process, among which methyltransferase-like 13 (METTL13) has been established to regulate cell fate, although its role in osteoporosis has yet to be determined.

Bone formation was assessed using micro-computed tomography and hematoxylin and eosin staining. Protein expression in bone tissues was examined immunohistochemically, and cellular mRNA and protein levels were determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. Cellular senescence was evaluated based on β-galactosidase staining, and osteogenic and adipogenic differentiation was examined using alkaline phosphatase, Alizarin Red S, and Oil Red O staining. Protein interactions and DNA binding were determined using co-immunoprecipitation and chromatin immunoprecipitation.

METTL13 expression was significantly enhanced in ovariectomy-induced senescent bone and BMSCs, whereas METTL13 knockdown markedly reversed etoposide-induced cellular senescence. By binding to forkhead box protein A1 (Foxa1), METTL13 promotes the preferential differentiation of BMSCs into adipocytes, as opposed to osteocytes. Moreover, Foxa1 had effects opposite to those of METTL13 on BMSC differentiation, inhibiting the nuclear entry of METTL13. Notably, blocking the nuclear import of Foxa1 suppressed the transcriptional expression of HES-1, which promoted the adipogenic differentiation of BMSCs and inhibited osteogenic differentiation.

Our findings in this study revealed the mechanisms whereby METTL13 promotes BMSC senescence and disrupts BMSC differentiation, on the basis of which, we identified the METTL13-Foxa1-HES-1 axis as a potential therapeutic target for treatment of osteoporosis.

Infective endocarditis (IE) related to opioid use disorder (OUD) and injection substance use is on the rise. Multidisciplinary care is recommended for individuals with substance-related IE, but little is known about the impact of this care.

A retrospective cohort study to evaluate the impact of a multidisciplinary endocarditis evaluation team (MEET) on outcomes for patients with IE and specifically OUD-related IE. The MEET is a clinical team from multiple specialities that collaboratively facilitates optimal hospital-based treatment, including addiction-related treatment.

The study compares a historical control group of hospitalized adults with OUD and OUD-related IE who did not receive the MEET intervention (treatment as usual [TAU] group) with a group of hospitalized adults with OUD and OUD-related IE who received the MEET intervention. The primary outcome is receipt of medication for OUD (MOUD) at hospital discharge. Secondary outcomes are receipt of OUD treatment referral, 30-day ED visits, 30-day hospital re-admission, all-cause mortality, recurrence of IE, and repeat IE-related surgery.

Nearly all patients in the MEET group (n = 68) were discharged on MOUD compared with the TAU group (n = 58) (98.5% vs. 56.9%) and received a referral for OUD treatment (97.1% vs. 74.1%). We were unable to detect a difference in 30-day ED visits and hospital readmissions, all-cause mortality, recurrent IE, and repeat IE-related surgery.

A multidisciplinary intervention was associated with improved OUD-related outcomes. No change was observed in health care utilization, all-cause mortality, or other IE-related outcomes.

Mitochondria are essential for cellular homeostasis, integrating various signals to control key cellular functions such as metabolism, apoptosis, inflammation, cell proliferation and redox balance. Given their multifaceted functions, it is not surprising that mitochondrial dysfunction has been implicated as a key contributor to the pathogenesis of numerous human diseases. Consequently, preserving mitochondrial integrity and functionality is vital for overall organismal health. Mitochondrial health is safeguarded by a sophisticated and tightly regulated network of quality control systems. These include mitochondrial proteostasis, which ensures proper protein folding and degradation; mitochondrial biogenesis, which governs the synthesis of new mitochondria; mitochondrial dynamics, encompassing fusion and fission processes; and mitophagy, the selective autophagic removal of damaged mitochondria. Additionally, these core systems are intricately connected to other crucial mitochondrial processes, such as the maintenance of mitochondrial DNA integrity, the regulation of cristae architecture, and the control of mitochondrial permeability transition, all of which are indispensable for optimal mitochondrial performance. Preclinical and clinical studies consistently demonstrate a strong link between impairments in these quality control mechanisms and both aging and the development of a wide spectrum of diseases. These include cancer, metabolic disorders, cardiovascular conditions, neurodegenerative diseases and autoimmune pathologies. In this review, we explore the different facets of mitochondrial quality control and discuss their implications in disease progression and aging. Furthermore, we highlight recent advances in interventions and therapies aimed at modulating mitochondrial quality control, providing an overview of their potential to mitigate disease burden and promote healthy aging.

Atypical antipsychotics (AAPs)-induced QT interval prolongation represents a major clinical safety challenge. Traditional mechanisms based solely on hERG (IKr) channel blockade cannot fully explain the heterogeneity of clinical phenotypes and severe arrhythmias during overdose. This study systematically evaluated the effects of representative AAPs at therapeutic and toxic concentrations on cardiomyocyte electrophysiological activities. Using whole-cell patch-clamp techniques, we recorded action potentials and major transmembrane ionic currents (IKr, IKs, IK1, Ito, and INa) in primary adult mouse ventricular myocytes exposed to five AAPs (olanzapine, quetiapine, clozapine, ziprasidone, and risperidone) at a moderate therapeutic concentration. Dose-responses for olanzapine and quetiapine across low, medium, and high concentrations were also analyzed. At therapeutic concentrations, all the five AAPs significantly prolonged 90% action potential duration (APD90). Olanzapine, clozapine, and risperidone also prolonged APD50, which was unlike quetiapine and ziprasidone. Ion current analysis revealed quetiapine and ziprasidone significantly inhibited IKr, whereas olanzapine, clozapine, and risperidone suppressed Ito. Olanzapine and clozapine additionally reduced IK1 and INa. At supratherapeutic concentrations, olanzapine and quetiapine concentration-dependently prolonged APD90 and non-selectively inhibited all measured currents. In conclusion, at therapeutic concentrations, AAPs delay ventricular repolarization via distinct ion channel blockades. At supratherapeutic doses, the loss of channel selectivity and synergistic multi-channel blockade constitute the core mechanism for malignant arrhythmias during drug overdose, highlighting the need to consider drug-specific multi-channel profiles in future clinical cardiac safety evaluations.

SIRT6 downregulation in atherosclerotic vascular endothelial cells (ECs) is exacerbated under diabetic conditions, and EC-specific Sirt6 knockout aggravates diabetic atherosclerosis progression. EC-specific Sirt6 knockout aggravates atherosclerosis progression through vasculature hyperpermeability and monocyte/macrophage accumulation in vessels. SIRT6 directly interacts with transcription factor zinc finger E-box binding homeobox 1 (ZEB1) for deacetylation/degradation, preserving ZEB1 at a low level for normal expression of tight junction protein claudin-1 in ECs to maintain endothelial barrier function for vascular homeostasis. Naringin, a natural flavonoid ZEB1 inhibitor, reverses the diabetes-exacerbated vascular endothelial dysfunction to attenuate atherosclerosis progression, offering a promising, novel therapeutic strategy for diabetic atherosclerotic cardiovascular diseases.

Myocardial ischemia/reperfusion (I/R) injury undermines the clinical benefit of percutaneous coronary intervention, with cardiac macrophages playing critical roles. Here, using spatial transcriptomics and flow cytometry, we identified adenylyl cyclase 7 (ADCY7) as a macrophage-specific regulator and potential therapeutic target in myocardial I/R injury, and validated its expression in patient samples. By establishing a macrophage depletion/reconstitution model, we demonstrate that macrophage Adcy7 deficiency significantly exacerbates myocardial I/R injury and cardiac dysfunction in male mice, whereas Adcy7 overexpression attenuates these effects. Macrophage Adcy7 deficiency also increases leukocyte infiltration and pro-inflammatory cytokine production. Mechanistically, transcriptomic and phosphoproteomic analyses reveal that ADCY7 activates cAMP-protein kinase A signaling, thereby inhibiting nuclear translocation of NF-κB and restraining the pro-inflammatory response. Combined with the macrophage depletion/reconstitution approach, we developed a photoactivated adenylyl cyclase system that alleviated cardiac inflammation and I/R injury. Our study identifies ADCY7 as a macrophage-intrinsic anti-inflammatory regulator and a promising therapeutic target for myocardial I/R injury.

Stroke remains a major global cause of death and disability, with many patients either missing the therapeutic window or responding poorly to current first-line treatments. Consequently, secondary neurological injury, driven predominantly by neuroinflammation, has emerged as a critical therapeutic target. Microglia rapidly sense post-stroke microenvironmental changes and adopt distinct inflammatory phenotypes that shape pathophysiological outcomes.

Accumulating evidence, including high-resolution spatial profiling and single-cell omics, positions mitochondrial dysfunction at the core of these responses. This review synthesizes recent findings on microglial mitochondrial dysfunction in stroke, introducing the concept of a microglial mitochondrial "storm center". In this model, reactive oxygen species (ROS) trigger an inflammatory cascade, while impairments in mitochondrial quality control (MQC) exacerbate pathogenic signaling. Metabolic reprogramming further sustains inflammatory polarization, influencing interactions with neurons, astrocytes, and endothelial cells.

This "storm center" provides a conceptual framework for developing strategies to mitigate secondary brain injury. Finally, this review highlights key molecular mechanisms, potential therapeutic targets, and translational opportunities, providing a stronger foundation for future stroke research and therapeutic innovation.

Vascular remodeling is a central pathological feature of cardiovascular diseases and is driven in part by vascular smooth muscle cell (VSMC) proliferation, migration, and phenotypic switching. The solute carrier family 7 member 5 (SLC7A5), a key amino acid transporter, has been implicated in cellular growth and metabolic regulation, but its role in vascular remodeling remains unclear. We investigated the contribution of SLC7A5 to VSMC activation and the underlying signaling mechanisms.

Differential expression analysis of the GSE220512 dataset revealed significant upregulation of Slc7a5 in mouse carotid arteries at Day 7 following wire injury compared with uninjured Day 0 controls (log₂FC = 2.39, adjusted P = 0.0064). In a rat carotid artery balloon injury model, SLC7A5 expression was upregulated and localized to the medial layer. In vitro, platelet-derived growth factor-BB (PDGF-BB) increased SLC7A5 expression in VSMCs. Functional studies showed that siRNA-mediated knockdown of SLC7A5 attenuated PDGF-BB-induced VSMC proliferation, migration, and phenotypic switching, as evidenced by reduced PCNA and MMP2 expression, decreased DNA synthesis, impaired migration, and partial restoration of α-smooth muscle actin expression. Mechanistically, SLC7A5 knockdown reduced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt without affecting total protein levels. Pharmacological inhibition of SLC7A5 using JPH203 produced similar effects in vitro and reduced neointimal hyperplasia and improved vascular function in vivo, with suppression of PI3K/Akt signaling.

These findings identify SLC7A5 as a critical regulator of VSMC activation and vascular remodeling. SLC7A5 promotes proliferative and migratory responses, at least in part through activation of the PI3K/Akt signaling pathway. Targeting SLC7A5 may represent a potential therapeutic strategy for vascular remodeling-associated cardiovascular diseases.

Volume-regulated anion channels (VRACs), formed by leucine-rich repeat-containing 8 (LRRC8) proteins, are ubiquitously expressed chloride channels essential for cell volume regulation and implicated in diverse physiological and pathological processes. Small-molecule VRAC inhibitors have been reported to modulate paracrine signaling, proliferation, differentiation, migration, and apoptosis, and have been patented for potential therapeutic applications in stroke, cardiovascular and metabolic diseases, and cancer. However, growing evidence indicates that many commonly used VRAC blockers exert substantial off-target effects and frequently fail to reproduce phenotypes observed after deletion of the essential VRAC subunit LRRC8A. Here, we systematically compared effects of several widely used pharmacological VRAC inhibitors with outcomes of molecular downregulation of LRRC8A in limiting proliferation of malignant glioblastoma cells derived from surgical specimens. NIH/3T3 fibroblasts served as a non-malignant control. In serum-containing media, structurally diverse VRAC blockers (DCPIB, DIDS, carbenoxolone, phloretin, and bromadiolone) reduced proliferation in a non-uniform manner, with potencies that did not correlate with reported VRAC affinities and varied markedly among cell lines. Radiotracer-based measurements of VRAC activity indicated that these discrepancies were largely attributable to binding of inhibitors to serum albumin. When experiments were repeated under serum-free conditions, all inhibitors except DIDS and phloretin induced extensive death of both malignant and non-malignant cells, confirmed by microscopy and LDH release assays. This cytotoxicity was accompanied by a marked reduction in intracellular ATP levels, consistent with previously reported mitochondrial uncoupling effects. In contrast, LRRC8A knockdown reduced proliferation without substantial cell death. Together, these findings demonstrate that most commercially available VRAC blockers limit proliferation and viability predominantly through VRAC-independent mechanisms. Under standard culture conditions, serum albumin masks much of their intrinsic cytotoxicity. These results underscore the need for rigorous molecular controls in pharmacological studies and provide basis for developing more selective and less toxic VRAC-targeting agents.