Key Takeaways & Executive Findings
- •• Metabolic reprogramming is a primary driver of disease initiation, progression, and therapeutic resistance, not just a passive consequence. • Multi-omics approaches reveal tissue-specific metabolic shifts underlying cardiometabolic syndrome, offering new therapeutic targets beyond symptom management. • In pregnancy, skeletal muscle undergoes structural and metabolic reprogramming, linking maternal insulin resistance to gestational diabetes mellitus. • Levosimendan protects against septic cardiomyopathy via Nrf2-dependent mitochondrial preservation, highlighting metabolic interventions for acute organ injury.
Abstract
For decades, cellular metabolism was viewed as a static network of biochemical pathways designed solely to produce ATP and fulfill basic energy needs. Classical pathophysiology frequently attributes systemic disorders, including cardiovascular disease, oncogenesis and tissue fibrosis, to structural defects, hormonal dysregulations or localized inflammation. However, advanced multi-omics frameworks have driven a paradigm shift, with metabolic reprogramming being recognized not merely as a passive consequence of disease but also as a primary driver of initiation, progression, and therapeutic resistance across human pathologies. This Special Issue, titled “Metabolic Reprogramming”, brings together 17 comprehensive studies alongside 3 New Phenomena exploring these transformations. The contributions span four interrelated thematic areas: (1) systemic cardiometabolic and gestational syndromes; (2) acute and chronic organ injury; (3) oncological metabolic dependencies; and (4) systemic organ-axis interdependencies. By integrating transcriptomics, metabolomics, single-cell deconvolution, and targeted biochemical analyses, these studies elucidate the precise molecular mechanisms governing metabolic remodeling.
1. Introduction
For decades, cellular metabolism was viewed as a static network of biochemical pathways designed solely to produce ATP and fulfill basic energy needs. Classical pathophysiology frequently attributes systemic disorders, including cardiovascular disease, oncogenesis and tissue fibrosis, to structural defects, hormonal dysregulations or localized inflammation. However, advanced multi-omics frameworks have driven a paradigm shift, with metabolic reprogramming being recognized not merely as a passive consequence of disease but also as a primary driver of initiation, progression, and therapeutic resistance across human pathologies [1,2].
Metabolic flexibility, the capacity to seamlessly adapt metabolic machinery to fluctuating environmental demands and nutrient availability, is fundamental to homeostasis [2]. When this adaptability fails, physiological processes are compromised. This Special Issue, titled “Metabolic Reprogramming”, brings together 17 comprehensive studies alongside 3 New Phenomena exploring these transformations. The contributions span four interrelated thematic areas at the forefront of biomedical innovation: (1) systemic cardiometabolic and gestational syndromes—driven by lifestyle changes, aging, and metabolic syndromes; (2) acute and chronic organ injury—including cardiomyopathy, heart failure, and vascular intimal hyperplasia; (3) oncological metabolic dependencies—exploring tumor survival and chemoresistance; and (4) systemic organ-axis interdependencies—the gut microbiota-metabolite axis and the intestinal-liver-kidney network. By integrating transcriptomics, metabolomics, single-cell deconvolution, and targeted biochemical analyses, these studies elucidate the precise molecular mechanisms governing metabolic remodeling.
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Jun Ren, Hartmut Schlüter, Marcel Kwiatkowski, Ling Lin (2026). Metabolic reprogramming—the nexus of cellular adaptations, organ crosstalk, and therapeutic innovations in human diseases. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2026110
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Frequently Asked Questions
What is metabolic reprogramming?
Metabolic reprogramming refers to the alterations in cellular metabolism that drive disease initiation and progression, beyond merely being a consequence of pathology. It involves shifts in metabolic pathways to support cell survival, proliferation, and therapy resistance.
How does metabolic reprogramming contribute to cardiometabolic syndrome?
Metabolic reprogramming in tissues like adipose, muscle, and liver leads to inefficient substrate utilization and decoupled metabolic pathways, contributing to insulin resistance, dyslipidemia, and hypertension, which collectively define cardiometabolic syndrome.
What role does metabolic reprogramming play in pregnancy?
During pregnancy, maternal skeletal muscle undergoes structural and metabolic reprogramming to modulate insulin sensitivity, ensuring adequate glucose supply to the fetus. Excessive reprogramming can lead to gestational diabetes mellitus, posing risks to both mother and offspring.
How does Levosimendan protect against septic cardiomyopathy?
Levosimendan, a Ca2+ sensitizer, attenuates sepsis-induced mitochondrial damage and inflammation via Nrf2 activation, thereby preserving cardiac function and reducing injury in septic cardiomyopathy.
What are the therapeutic implications of targeting metabolic reprogramming?
Targeting metabolic reprogramming offers a novel approach to treat diseases by correcting underlying metabolic inflexibility rather than just managing symptoms, potentially improving outcomes in cardiovascular diseases, cancer, and metabolic disorders.
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