Search Results (702)

Background/Objectives: Prior studies linking fatty liver-related phenotypes to aortic disease have mainly focused on abdominal aortic aneurysm and used earlier nomenclature. We examined associations of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic risk factor (CMRF) count with aortic aneurysm and aortic dissection. Methods: We analyzed 240,074 adults from the 2009–2010 Korean National Health Insurance Service health-screening database after exclusions. Steatotic liver disease was assessed using the Fatty Liver Index, and MASLD was defined as steatotic liver disease with at least one CMRF. Outcomes were identified using claims-based International Classification of Diseases, 10th Revision codes. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. Results: Over a median follow-up of 9.6 years, 1018 aortic aneurysm events and 285 aortic dissection events were recorded. Incidence rates in the MASLD and reference groups were 0.54 versus 0.21 for aortic aneurysm and 0.15 versus 0.04 for aortic dissection per 1000 person-years. Compared with individuals without steatotic liver disease and without CMRFs, MASLD was associated with higher risks of aortic aneurysm (adjusted HR, 1.58; 95% CI, 1.14–2.18) and aortic dissection (adjusted HR, 2.12; 95% CI, 1.03–4.38). Compared with individuals without steatotic liver disease but with CMRFs, MASLD remained associated with aortic aneurysm, but not aortic dissection. Higher CMRF count was associated with aortic aneurysm. Conclusions: MASLD and higher CMRF count were associated with incident aortic aneurysm, whereas findings for aortic dissection were less consistent. Further studies with more precise liver and aortic phenotyping are warranted. Full article

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction-associated steatohepatitis (MASH) arise in the setting of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This review examines how mitochondrial dysfunction participates in the transition from lipid accumulation to hepatocyte injury, inflammation, and fibrosis, and how evidence from human, animal, and in vitro studies should be interpreted. Methods: We provide a narrative synthesis of mechanistic, translational, and clinical studies on hepatic mitochondrial metabolism, fatty acid oxidation, oxidative phosphorylation, redox stress, organelle crosstalk, mitophagy, mitochondrial biogenesis and proteostasis, mitochondrial danger signals, the gut-liver-mitochondria axis, and mitochondria-related therapeutic strategies. Results: In early metabolic overload, mitochondrial oxidation may increase as an adaptive response. With persistent substrate pressure, this adaptation can become inefficient, with impaired fatty acid disposal, less efficient oxidative phosphorylation, reactive oxygen species production, redox imbalance, defective mitochondrial quality control, altered mitochondrial biogenesis, mitochondrial unfolded protein response (UPRmt)-related proteostatic stress and mtDNA instability. Mitochondrial DNA and RNA released from damaged organelles may also activate cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), inflammasome, and RNA-sensing pathways, linking hepatocyte stress to macrophage activation, stellate cell activation, extracellular matrix deposition, and fibrosis. Conclusions: The current evidence supports mitochondria as a stage-dependent amplifier of metabolic liver injury rather than a uniform initiating event. Clinically, the strongest evidence remains with upstream metabolic unloading and liver-directed metabolic therapy, whereas direct mitochondrial restoration and quality-control targeting remain promising but less mature. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe, progressive liver disease lacking effective therapies. Disulfiram (DSF), an FDA-approved medication for alcohol dependence, exhibits diverse biological activities beyond its primary indication. This study aimed to evaluate whether DSF holds intervention promise for MASH and to unravel the underlying molecular mechanism. The efficacy of DSF was assessed in a mouse model of MASH induced by a choline-deficient, L-amino acid-defined diet, as well as in hepatocytes exposed to free fatty acids (FFAs) to trigger lipotoxicity. RNA-seq analysis combined with bioinformatic approaches was performed to identify key pathways and hub genes. Mechanistic validation was carried out using Western blotting and qPCR. Computational predictions suggested that DSF may influence insulin resistance, inflammation, autophagy-related markers, and lipid metabolism. In FFAs-treated hepatocytes, DSF administration dose-dependently reduced lipid accumulation and lipotoxicity. Consistently, in MASH mice, DSF administration significantly lowered elevated serum ALT (35%) and AST (40%) levels and the absolute hepatic triglyceride content (reduced from 1 to 0.5 μg/mg protein), and markedly attenuated hepatic steatosis, inflammation, fibrosis, and oxidative stress. Of note, RNA-seq analysis revealed that DSF modulated autophagy-related pathways and identified Aurora kinase A (AURKA) as a central downregulated hub gene. Mechanistically, DSF suppressed AURKA expression, which in turn led to changes in autophagy-related markers. These changes in autophagy-related markers were functionally coupled to a reduction in lipotoxicity. Collectively, DSF alleviates MASH by inhibiting AURKA, thereby relieving AURKA-mediated suppression of autophagy-related markers, which was associated with diminishing lipotoxicity, and ultimately achieving broad suppression of disease progression. Thus, DSF represents a promising hepatoprotective candidate for the intervention of MASH. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and is driven by complex metabolic and inflammatory disturbances. Extra virgin olive oil (EVOO), a hallmark of the Mediterranean diet, contains numerous bioactive compounds that may exert beneficial effects on liver and cardiometabolic health. This preliminary study investigated the interactions of selected EVOO-derived compounds, with molecular targets implicated in MASLD using an integrated in silico approach. Methods: Phenolic compounds, secoiridoids, fatty acids, sterols, squalene, and vitamin E were evaluated. Physicochemical properties, drug-likeness, and pharmacokinetic profiles were predicted using ADMETlab 3.0. Molecular docking analyses were performed against liver X receptors (LXRα and LXRβ), peroxisome proliferator-activated receptors (PPARα and PPARγ), hydroxymethylglutaryl-CoA reductase, cyclooxygenase-1, and cyclooxygenase-2. Binding modes were further examined by three-dimensional interaction analyses. Results: The investigated compounds displayed heterogeneous physicochemical and pharmacokinetic profiles. Oleuropein, oleacein, and oleocanthal demonstrated the most consistent binding patterns across targets involved in lipid metabolism, inflammation, and cardiometabolic regulation. In contrast, highly lipophilic compounds, including squalene, β-sitosterol, and vitamin E, frequently achieved high docking scores but formed fewer biologically relevant interactions. Conclusions: EVOO phenolics, particularly oleuropein, oleacein, and oleocanthal, emerged as promising multi-target modulators of MASLD-related pathways, supporting the potential role of EVOO in MASLD prevention and management. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited treatment options. Here, we demonstrate that fucoxanthin (FUCO), a natural marine carotenoid, attenuates free fatty acid (FFA)-induced hepatocellular steatosis and inflammatory responses in vitro by targeting the EGR2-CD36 axis (EGR2, early growth response protein 2; CD36, cluster of differentiation 36). In FFA-induced hepatocyte models (HepG2, Hep3B, and AML12), FUCO significantly reduced lipid accumulation and inflammatory markers without cytotoxicity. Mechanistic studies revealed that FUCO specifically inhibited fatty acid uptake and transport by downregulating CD36, while triglyceride (TG) degradation remained unaffected. RNA sequencing identified EGR2 as a master regulator induced by FFA and suppressed by FUCO. Functional validation showed that EGR2 overexpression completely blocked FUCO’s lipid-lowering effects and restored CD36 expression, confirming that FUCO acts through EGR2-dependent CD36 inhibition. Bioinformatic analysis further supported EGR2-mediated regulation of CD36 via tumor necrosis factor (TNF) and sterol regulatory element-binding factor (SREBF) pathways. Collectively, our findings establish EGR2 as a critical molecular target for FUCO and provide mechanistic insights that may support its further evaluation in preclinical models for MASH therapy. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most prevalent chronic liver disease worldwide, imposing a severe public health burden. Its core pathological hallmark is excessive hepatic lipid accumulation driven by systemic metabolic dysregulation. Concomitant hepatocellular injury impairs hepatic lactate clearance, leading to aberrant lactate buildup in the liver microenvironment. However, the causal role of lactate in exacerbating liver lipid metabolism dysfunction and driving the progression of MASLD remains unclear. Methods: First, we performed a comprehensive bioinformatic analysis of publicly available transcriptomic datasets. Mining of the Gene Expression Omnibus (GEO) database showed that lactate dehydrogenase (LDH) expression was significantly upregulated in liver tissues from both metabolic dysfunction-associated fatty liver disease (MASLD) patients and MASLD mouse models. Next, network pharmacology approaches were employed to predict putative molecular targets that could mediate lactate’s biological effects. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these candidate targets were predominantly enriched in pathways governing fatty acid metabolism and long-chain fatty acid transport. Molecular docking and molecular dynamics simulations further suggested possible interactions and supported the prioritization of cluster of differentiation 36 (CD36) as candidate lipid metabolism regulators potentially involved in lactate-mediated effects. Finally, liver-specific Ldha knockdown mice (AAV8-TBG-shRNA) and free fatty acid-induced steatotic AML12 hepatocytes were used to investigate the functional relevance of these findings in vivo and in vitro. Results: Network pharmacology analyses preliminarily identified the PPAR signaling pathway as a candidate pathway potentially linking lactate to MASLD. Experimental results showed that exogenous lactate administration was associated with significantly increased lipid accumulation in steatotic AML12 hepatocytes and the livers of MASLD mice, manifested as elevated triglyceride levels and enhanced lipid droplet formation, accompanied by upregulated expression of PPARγ and CD36. Conversely, inhibiting endogenous lactate production or silencing PPARγ or CD36 attenuated this lipid-accumulation phenotype and significantly reduced intracellular triglyceride levels. Conclusions: In conclusion, these findings indicate that lactate exposure is associated with hepatic lipid accumulation and upregulation of the PPARγ/CD36 axis. Pharmacological inhibition or silencing of PPARγ or CD36 attenuates this phenotype, suggesting that this pathway may contribute to lactate-associated hepatic steatosis and potentially accelerate MASLD progression. Full article

Background/Objectives: The aim of this study is to evaluate the relationship between adherence to the Mediterranean diet and intestinal microbiota metabolite trimethylamine N-oxide (TMAO) levels, systemic inflammation markers, and oxidative stress parameters in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: MASLD patients whose fatty liver and fibrosis severity were determined with FibroScan and a healthy control group were included in the study. In addition to the routine biochemical parameters, serum TMAO levels, inflammatory cytokines (IL-6, IL-10, TNF-α), and oxidative stress indicators (malondialdehyde, glutathione, and MDA/GSH ratio) of all participants were measured. In comparing these parameters between fibrosis groups, adjustment for potential confounding variables (age, BMI, sex, comorbidity, relevant medication use, MEDAS score, and physical activity) was performed. Following anthropometric evaluations, the adherence levels of the participants to the Mediterranean diet were determined by the Mediterranean Diet Adherence Screening Scale (MEDAS), and their physical activity levels were determined through the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Results: Individuals diagnosed with MASLD had significantly lower adherence to the Mediterranean diet and lower physical activity levels compared with healthy controls. Among the inflammatory parameters, IL-6 levels were significantly higher in the advanced fibrosis group than in the early-stage and significant fibrosis groups, while TNF-α levels were significantly higher in the advanced fibrosis group than in the early fibrosis group. No significant differences were observed among the groups in TMAO, IL-10, GSH levels, or the MDA/GSH ratio; however, among the oxidative stress markers, MDA levels were significantly higher in the early fibrosis group than in the significant fibrosis group. Conclusions: In MASLD patients, fibrosis severity was associated with alterations in TMAO, inflammatory, and oxidative stress markers, with increased TNF-α and IL-6 levels reflecting a high inflammatory burden as fibrosis progressed. Lower TMAO levels in fibrosis groups likely reflect reduced hepatic FMO3 activity, lower fish intake, and medication use, while elevated MDA levels in early-stage fibrosis suggest that lipid peroxidation may be more prominent in the initial phases of disease. Mediterranean diet adherence and physical activity were inversely associated with pro-inflammatory markers and MASLD severity, being highest in the control group, suggesting a potential protective role for these lifestyle factors in MASLD progression. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health burden driven by complex interactions among hepatic lipid accumulation, insulin resistance, chronic inflammation, and mitochondrial dysfunction. Exercise remains the cornerstone of lifestyle therapy for MASLD/MASH; however, its therapeutic benefits extend well beyond weight reduction and involve coordinated molecular adaptations across multiple organ systems. In this review, we introduce hepatic mitochondrial reprogramming as a conceptual framework describing the coordinated remodeling of mitochondrial energetics, quality-control pathways, and redox homeostasis that collectively restore metabolic flexibility and hepatocellular resilience. Exercise activates key metabolic regulators, including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuin signaling, promoting mitochondrial biogenesis, fatty acid oxidation, oxidative phosphorylation, and mitophagy while suppressing hepatic lipogenesis and oxidative injury. Skeletal muscle-derived myokines, alterations in gut microbial metabolism, and thyroid hormone signaling converge upon hepatic mitochondrial function through complementary endocrine and metabolic pathways. Together, these adaptations reduce hepatic steatosis, lipotoxicity, inflammation, and fibrogenesis while improving insulin sensitivity and metabolic flexibility. Emerging evidence further suggests that exercise-induced mitochondrial remodeling may complement pharmacologic therapies targeting hepatic metabolism, including thyroid hormone receptor-β agonists. Although multi-omics technologies continue to expand our understanding of these adaptive responses, the present review emphasizes the underlying molecular and physiological mechanisms through which exercise remodels hepatic mitochondrial function. We propose that exercise acts as a systems-level mitochondrial remodeling stimulus integrating skeletal muscle-, gut-, and thyroid-derived signals to improve hepatic metabolism and attenuate MASLD/MASH progression. This conceptual framework provides a mechanistic basis for precision exercise prescriptions and future combination therapeutic strategies targeting mitochondrial health. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the leading cause of hepatocellular carcinoma (HCC) globally. HCC surveillance is currently restricted to patients with cirrhosis, leaving those without cirrhosis, who present with more advanced disease and poorer outcomes without adequate risk stratification tools. This study compared lipid profiles across MAFLD and MAFLD-related HCC (MAFLD-HCC) patients, with and without cirrhosis, to characterise metabolic dysregulation underlying non-cirrhotic MAFLD-HCC (ncMAFLD-HCC). Plasma and liver lipidomic profiles were obtained from 221 patients (140 MAFLD, 66 cirrhotic MAFLD-HCC (cMAFLD-HCC), and 15 ncMAFLD-HCC) using untargeted liquid chromatography mass spectrometry. Univariate, multivariable and enrichment analyses were performed for statistically determining the lipid profile difference between the groups. Seventy percent of lipid classes were more abundant in MAFLD than in ncMAFLD-HCC and cMAFLD-HCC. Multivariate analysis revealed distinct lipid profiles across the three groups in both plasma and liver. Over 100 lipid species including diglyceride (DAG), sphingomyelin (SM), triglyceride (TG), dihydroceramide (DHCer), and linoleic acid derivatives were differentially expressed in ncMAFLD-HCC versus MAFLD, with enrichment in pathways such as glycerolipid metabolism, G-protein signalling, MAPK signalling, EGFR-TKI resistance pathway, implicated in HCC development. ncMAFLD-HCC exhibits a distinct lipid signature, offering preliminary mechanistic insight and a foundation for non-invasive biomarker development. Full article

The rising burden of diabetic kidney disease (DKD) and its associated lipid abnormalities underscores the need for new mechanistic insights. Uromodulin, a kidney-enriched protein, has been associated with metabolic disorders in human studies, yet its functional role in systemic lipid metabolism remains elusive. In this study, transcriptomic datasets were analyzed to investigate uromodulin expression and biological function in DKD. Subsequently, a diabetic model was induced in UMOD^+/+ and UMOD^−/− rats using a combination of a high-fat diet, unilateral nephrectomy, and streptozotocin to assess renal and metabolic phenotypes. Public RNA-seq data indicated that uromodulin expression was downregulated in DKD and was enriched in the fatty acid metabolism pathway. At baseline, UMOD^−/− rats resembled UMOD^+/+ rats in terms of growth, routine serum lipids, and major organ function. However, in diabetes, UMOD^−/− rats exhibited higher mortality and pronounced hyperlipidemia. Hyperlipidemia occurred prior to the onset of renal dysfunction. Of note, this exacerbated lipid dysregulation represented a lipodystrophy-like phenotype rather than secondary changes in the pancreas, liver, or circulating cytokines (IL-6, IL-1β, and TNF-α). Moreover, UMOD^−/− rats displayed exacerbated tubular injury and enhanced renal lipid accumulation in DKD relative to UMOD^+/+ rats. Collectively, uromodulin protects diabetic rats from death, prevents epididymal white adipose tissue from browning, and attenuates kidney injury. Our findings identify uromodulin as a novel regulator of the kidney–adipose axis. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to atrial fibrillation (AF); however, its relationship with specific AF subtypes remains unclear. This prospective, single-center, observational case–control study investigated whether MASLD is independently associated with AF presence and its subtypes. Materials: A total of 327 participants were analyzed, including 119 controls and 208 patients with AF. Comprehensive clinical history, anthropometric measures, laboratory testing, 24 h Holter ECG, and echocardiography were performed. Clinically inferred MASLD was defined according to the current EASL–EASD–EASO guidelines using clinical and non-invasive indices (Hepatic Steatosis Index, Fatty Liver Index, Fibrosis-4 Index). No liver biopsy or imaging confirmation of steatosis or fibrosis was performed, and therefore, the diagnosis represents a clinically inferred (“probable”) MASLD. To minimize systematic bias and improve baseline comparability between groups, propensity score matching and complementary regression analyses were applied. Results: Overall probable MASLD prevalence did not differ between AF and controls (42% vs. 44%, p = 0.742). A clear phenotypic gradient emerged across subtypes: lowest in permanent AF (PermAF, 27.1%) versus paroxysmal (47.1%) and persistent AF (51.4%) (p = 0.021). PermAF exhibited the most advanced comorbidity—highest CHF (78.6%), CKD (71.4%), HFpEF (48.6%), FIB-4 (median 2.67), the lowest TG/HDL–cholesterol ratio (1.93 vs. 3.32; p < 0.001), and progressive renal impairment. Statin therapy reached 80% in clinically inferred MASLD-positive PermAF. The elevated FIB-4 observed in PermAF must be interpreted with explicit caution: this group was substantially older (median 79.5 years) and carried the highest burden of chronic heart failure and chronic kidney disease; therefore, in this subgroup, FIB-4 most plausibly reflects age and cardio-renal comorbidity rather than histologically confirmed hepatic fibrosis. After matching, MASLD was not an independent predictor of AF presence (OR = 0.96; 95% CI: 0.59–1.46) or its clinical severity. Conclusions: Probable MASLD, defined by clinical and non-invasive indices, was not independently associated with AF in this cohort, but AF subtypes exhibited a clear phenotypic gradient—from a metabolically driven profile in early AF to a cardio-renal and fibrotic pattern in advanced, elderly AF. Elevated FIB-4 values in PermAF most plausibly reflect age and cardio-renal comorbidity rather than true histologically confirmed hepatic fibrosis. These findings support a phenotype- and population-dependent MASLD–AF relationship and underscore the need for imaging- and histology-verified longitudinal studies. Full article

Objectives: Occupational physical activity (OPA) and leisure-time physical activity (LTPA) have contrasting health effects, a phenomenon known as the “physical activity paradox.” We explored the domain-specific associations between physical activity and non-alcoholic fatty liver disease (NAFLD). Methods: This cross-sectional study included 20,584 Korean workers (10,846 women). Physical activity was assessed using the Global Physical Activity Questionnaire, and NAFLD was assessed using the hepatic steatosis index and the presence of metabolic dysfunction. Logistic regression models were employed to explore the association between each domain of physical activity and NAFLD. The associations are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Results: The prevalence of NAFLD was 30.6% in men and 18.1% in women. For male workers, ≥300 min/week of OPA was positively associated with NAFLD (OR: 1.41; 95% CI: 1.15–1.72), while ≥300 min/week of LTPA was negatively associated with NAFLD (OR: 0.79; 95% CI: 0.67–0.93). In female workers, LTPA was negatively associated with NAFLD from a lower level (OR: 0.63; 95% CI: 0.52–0.78 for 1–149 min/week; OR: 0.71; 95% CI: 0.56–0.89 for 150–299 min/week; OR: 0.58; 95% CI: 0.43–0.78 for ≥300 min/week of LTPA), while OPA had no clear association with NAFLD. Conclusions: OPA and LTPA were differentially associated with NAFLD in workers. Domain- and sex-specific effects of physical activity should be considered for the prevention and management of NAFLD. Full article

Cardiometabolic diseases are increasingly understood as disorders involving compartment-specific redox disruption rather than a uniform excess of reactive oxygen species. This narrative review synthesizes evidence for a proposed gut microbiota–mitochondria ferroptosis framework in which dysbiosis-derived lipopolysaccharide, trimethylamine N-oxide, short-chain fatty acids, bile acids, and tryptophan metabolites may modulate mitochondrial reactive species production, antioxidant defenses, iron handling, lipid peroxide detoxification, and inflammatory signaling. The reference set was assembled through searches of PubMed and Web of Science Core Collection, supplemented by targeted Google Scholar searches and citation chaining during manuscript preparation and revision through June 2026 and was organized around microbial metabolites, mitochondrial redox biology, ferroptosis pathways, disease-specific evidence, and redox-targeted interventions. Because this is a narrative synthesis rather than a systematic review, the framework should be interpreted as hypothesis-generating rather than as a systematically validated pathological model. Across atherosclerosis, diabetic cardiomyopathy, metabolic dysfunction-associated steatotic liver disease, obesity-associated insulin resistance, chronic kidney disease, and cardiorenal metabolic injury, the most consistent mechanistic links involve mtROS, impaired mitophagy, glutathione/GPX4 and SLC7A11 dysfunction, ACSL4-dependent lipid peroxidation, Nrf2 signaling, NLRP3 activation, and cGAS-STING-associated inflammation, although human causal evidence remains uneven. Importantly, much of the current literature supports local links within this sequence rather than a fully verified dysbiosis–metabolite–mitochondria ferroptosis–organ dysfunction chain in the same study. We therefore emphasize evidence tiers, terminology discipline, and biomarker requirements when interpreting ferroptosis-sensitive injury. Polyphenols, flavonoids, probiotics, postbiotics, melatonin, CoQ10-related strategies, mitochondria-targeted antioxidants, and ferroptosis-sensitive approaches may be most translatable when paired with microbiome, metabolomic, lipidomic, pharmacokinetic, and redox biomarkers. Full article

Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease. Full article

Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent and now recognized as a systemic syndrome with diverse clinical phenotypes and multiorgan involvement. The predominant clinical phenotype has evolved from patients with isolated hypertensive heart disease to individuals with cardiometabolic (CM) abnormalities [obesity, insulin resistance, increased waist circumference (a surrogate for visceral adiposity), dyslipidemia, type 2 diabetes, and hypertension] that result in metabolic alterations leading to CM-HFpEF. Indeed, CM-HFpEF and metabolic dysfunction-associated fatty liver disease are recognized as two sides of the same coin. Chronic systemic inflammation is a defining pathophysiologic feature of CM-HFpEF, with visceral adipose tissue serving as a central driver. In this regard, lifestyle changes, including diet and exercise, are crucial for managing HFpEF. Several recent studies have shown that exercise training (aerobic and resistance combined) with or without calorie restriction is an effective therapeutic management strategy for improving exercise capacity, physical function, and quality of life in patients with clinically stable HFpEF. Also, the pharmacologic interventions that have proven beneficial in HFpEF so far (sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists) are effective due to their metabolic protective effects. In this review, we outline the current available evidence on lifestyle interventions in HFpEF management and therapeutics, discussing their modalities and potential mechanisms. Full article