Mechanisms for Regulatory Effects of Exercise on Metabolic Diseases from the Lactate–Lactylation Perspective

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3469 - 3469

Published: April 8, 2025

Metabolic diseases, including cardiovascular type 2 diabetes mellitus (T2DM), osteoporosis, and non-alcoholic fatty liver disease (NAFLD), constitute a major global health burden associated with chronic morbidity mortality. Lactate, once considered as metabolic byproduct, has emerged key regulator of cellular reprogramming through lactylation, novel post-translational modification (PTM) that dynamically couples flux to chromatin remodeling. Lactylation exerts dual regulatory roles signaling molecule via GPR81/GPR4-mediated pathways substrate for the covalent histones enzymes. Pathologically, hyperlactatemia suppresses mitochondrial biogenesis, driving cardiomyopathy epigenetic silencing oxidative metabolism genes. Conversely, exercise-induced lactate surges transiently enhance insulin sensitivity AMPK/PGC-1α/GLUT4 signaling, resolve inflammation GPR81-mediated M2 macrophage polarization, restore function lactylation-dependent pathways. This review delineates lactylation spatiotemporal rheostat: dysregulation perpetuates disorders, whereas acute exercise-mediated remodels transcriptional networks homeostasis. Future research should integrate multiomics clarify lactylation’s dynamics, tissue-specific thresholds, metabolism–immunity interactions, metabolic–epigenetic crosstalk precision management diseases.

Language: Английский

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SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-catenin

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 8, 2025

Language: Английский

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Diallyl Trisulfide From Garlic Regulates RAB18 Phase Separation to Inhibit Lipophagy and Induce Cuproptosis in Hepatic Stellate Cells for Antifibrotic Effects

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Abstract Liver fibrosis, a common pathological process, severely impacts human health, yet effective treatments are lacking. Cuproptosis, newly discovered form of cell death induced by copper ions, triggers cytotoxic stress through sulfenylated protein oligomerization and may offer novel therapeutic strategy for liver fibrosis. However, the mechanisms underlying cuproptosis in fibrosis not well understood. During progression, hepatic stellate cells (HSCs) activate, proliferate, secrete extracellular matrix components, contributing to Activated HSCs also undergo lipophagy, degradation lipid droplets. The study shows that Ras‐related Rab‐18 (RAB18), involved metabolism, inhibits upregulates Carnitine palmitoyltransferase 1A (CPT1A), promotes succinylation dihydrolipoamide dehydrogenase (DLD) at site K320, triggering HSCs. Diallyl trisulfides (DATs), garlic‐derived compound, induces phase separation RAB18 mitochondrial‐associated membrane structures (MAMs) formation, further accelerating separation. DATs selectively protects hepatocytes while activating Interfering with expression reverses DATs‐induced inhibition lipophagy cuproptosis. These findings, confirmed primary cells, (LX2), rodent models clinical samples, suggest DATs, targeting inducing its separation, subsequently inhibit promote cuproptosis, making it promising approach

Language: Английский

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Dietary and pharmacological energy restriction and exercise for healthspan extension

Trends in Endocrinology and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

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