Metabolic stress within one organ can have consequences far beyond its site of origin. In metabolic dysfunction-associated steatotic liver disease (MASLD), reactive carbonyl species, purine metabolites, and nitric oxide-related intermediates provide a basis for examining how metabolic disturbances may extend across tissues. Selected metabolites may act as systemic relay nodes when their production, persistence, and transport permit exposure beyond the source tissue. A broadly minutes-to-hours timescale offers a useful starting point for this hypothesis, while chemical form, reactivity, tissue uptake, and clearance determine the reach of each candidate. Plasma disappearance, whole-body elimination, intracellular persistence, and covalent-adduct persistence describe distinct processes that shape the interpretation of measured exposure. Mechanistic studies, analytical measurements, and clinical interventions together inform the links between local stress and distant effects. Emerging AI and multi-omics approaches may help characterize the resulting metabolic heterogeneity. Viewed through this framework, metabolite kinetics become a bridge between molecular mechanisms and candidate approaches to patient stratification, connecting the duration and distribution of exposure with potential sites of intervention.
The increasing prevalence of type 2 diabetes mellitus (T2DM) represents a significant public health challenge with serious implications for cancer incidence and treatment. Currently affecting over 400 million individuals worldwide, T2DM is characterized by chronic hyperglycemia and insulin resistance, which contribute to a pro-tumorigenic environment. This review seeks to elucidate the complex relationship between diabetes medications and cancer treatment, emphasizing how various agents, including metformin, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, thiazolidinediones (TZDs), and sodium–glucose cotransporter 2 (SGLT2) inhibitors, interact with critical signaling pathways involved in cancer progression. Evidence suggests that these medications can modulate oncogenic pathways such as AMPK/mTOR, insulin/IGF signaling, and Nuclear factor kappa B (NF-κB), leading to either inhibition or stimulation of tumor growth and survival depending on the drug class and biological context. For instance, metformin activates AMPK, inhibiting mTOR and promoting apoptosis, while TZDs exert anti-inflammatory effects that may reduce obesity-related cancer risks. Conversely, some DPP-4 inhibitors have been associated with pro-tumorigenic effects under certain conditions. Given the intricate interplay among diabetes, obesity, and cancer, understanding the effects of antidiabetic therapies on tumor biology is crucial for refining treatment strategies. This review consolidates current findings on the cellular and molecular impacts of major T2DM drug classes on cancer, highlighting their potential benefits and limitations. In conclusion, the findings presented in this analysis are intended to enhance treatment strategies and shape future research initiatives aimed at effectively addressing the complexities of managing patients who are concurrently affected by diabetes and cancer.
Pancreatitis is a complex inflammatory condition of the pancreas and can be classified into acute pancreatitis (AP) and chronic pancreatitis (CP). The pathogenesis of the disease remains unclear, and effective preventive or therapeutic strategies are currently lacking. Non-coding RNA (ncRNA) regulatory networks consist primarily of miRNAs, lncRNAs, and circRNAs, which precisely regulate gene expression through complex interactions and play a key role in fibrosis and inflammation. In terms of AP, ncRNAs could modulate the activity of pancreatic acinar cells, autophagic flux, inflammatory cell infiltration and the integrity of the intestinal mucosal barrier, which regulates local pancreatic and systemic inflammation. During the progression of CP, ncRNAs mediate the pancreatic persistent inflammation and collagen deposition by regulating the interactions between pancreatic stellate cells and immune cells. ncRNAs serve as promising non-invasive biomarkers for pancreatitis, enabling early diagnosis, severity stratification, complication prediction and differential diagnosis between CP and pancreatic cancer. Therapeutically, ncRNAs represent potential precision intervention targets due to their high regulatability and specificity, although ncRNA-based therapies currently remain at the preclinical stage. Key challenges such as delivery efficiency and targeting specificity must be addressed to facilitate clinical translation. Overall, ncRNAs offer a novel avenue for improving the clinical management of pancreatitis.
Epigenetic regulation is intimately linked to cellular metabolism, enabling environmental and nutritional cues to shape gene expression programs through dynamic modifications of chromatin structure. This metabolism-epigenetics interface is mediated, in part, by the dependence of chromatin-modifying enzymes on key metabolites, including S-adenosylmethionine (SAM), acetyl-CoA, UDP-GlcNAc, and α-ketoglutarate, which serve as substrates or cofactors for DNA and histone modifications. Among these regulators, EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), has emerged as a key mediator linking metabolic state to epigenetic regulation by translating metabolic inputs into changes in chromatin architecture and gene expression. EZH2 governs developmental cell fate through H3K27me3-mediated gene repression and is frequently dysregulated in cancer, where it promotes dedifferentiation, tumor progression, and metabolic reprogramming.Importantly, EZH2 activity is itself modulated by cellular metabolic status through posttranslational modifications, including phosphorylation, acetylation, methylation, ubiquitination, and O-GlcNAcylation, which influence its stability, catalytic activity, and chromatin-binding capacity. These modifications are responsive to nutrient availability and signaling pathways involving glucose, SAM, NAD+, and other metabolic intermediates. Consequently, disruption of this finely tuned regulatory network can contribute to developmental abnormalities, metabolic dysfunction, and oncogenesis.In this review, we examine the molecular mechanisms governing EZH2 regulation and discuss how metabolic control of EZH2 shapes chromatin dynamics, cell fate decisions, and disease pathogenesis. Elucidating how metabolic signals modulate EZH2 activity will advance our understanding of development and disease while uncovering potential therapeutic opportunities to target metabolism-driven epigenetic dysregulation.
