Background: Lactylation, a post-translational alteration facilitated by lactic acidderived lactyl-CoA, has emerged as an epigenetic regulator that alters gene expression in macrophages. Emerging data situates lactylation at the nexus of metabolic flux and immune cell destiny, especially in tumor and inflammatory microenvironments.

Main text: Lactylation is significantly linked to tumor progression and the polarization of macrophages towards the M2 phenotype, a condition that exacerbates cancer and associated inflammation. Modulating lactylation levels can alter the M1/M2 balance, hence affecting the progression of cancer and inflammatory illnesses. These findings identify lactylation as aregulator that can either suppress or enhance tumor development and the related inflammatory response, contingent upon the context and degree of the change.

Conclusion: This review systematically elucidates the role of lactylation in directing macrophage polarization in the context of cancer and associated inflammation. The aggregated data suggest that targeting lactylation constitutes an innovative therapeutic strategy for regulating immune cell activity and managing the advancement of cancer and related inflammatory conditions.

Background: The metabolic syndrome encompasses a state of inflammation and metabolic dysfunction, possibly mediated via a disturbed intestinal barrier. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as liraglutide, have shown promising anti-inflammatory effects beyond glucose lowering and weight loss, but the underlying mechanism remains to be elucidated. We hypothesised that GLP-1RAs improve the intestinal barrier function and overall inflammatory status by direct gene activation in mucus-secreting Brunner's glands in the mouse duodenum, known for their high density of glucagon-like peptide-1 receptors (GLP-1Rs).

Methods: Using bulk RNA sequencing, in situ hybridisation, and immunohistochemistry, we analysed the change in the genetic phenotype of mouse Brunner's gland cells following GLP-1R activation by liraglutide.

Results: We show that liraglutide induces a novel and robust upregulation of the gene for the Cystic fibrosis transmembrane conductance regulator, Cftr, in Brunner's glands as a part of an overall genetic phenotype involved in ion channel activity, mucus secretion, and hydration via GLP-1R activation. Additionally, we found a robust upregulation of the genes Muc5b, Il33, Ren1, and Vldlr in Brunner's glands.

Conclusion: Collectively, our results imply an enhanced mucus response from Brunner's glands following GLP-1R activation, which might play a role in the effect of GLP-1.

Background: The emergence of single-cell RNA sequencing (scRNA-seq) technology has revolutionized our capacity to study cell functions in complex tissue microenvironments. Traditional transcriptomic approaches, such as microarrays and bulk RNA sequencing, lacked the resolution to distinguish signals from heterogeneous cell populations or rare cell types, limiting their clinical utility. Since 2009, scRNA-seq has evolved as a new and powerful tool for revisiting somatic evolution and functions under physiological or pathological conditions.

Main Topics Covered: This review focus on elaborating on the clinical applications of scRNA-seq technology, with a particular emphasis on the application of scRNA-seq methods in revisiting the somatic cell evolution in human diseases. We further provide a snapshot of the scRNA-seq applications in biomarker discovery and drug development, current challenges associated with the technology, and future directions.

Conclusions: With the recent progresses in single cell and spatial transcriptome technologies, scRNA-seq enables a deeper understanding of the complexity of human diseases. The integration of AI and machine learning algorithms into big data analysis offers hope for overcoming these hurdles, potentially allowing scRNA-seq and multi-omics approaches to bridge the gap in our understanding of complex biological systems and advances the development of precision medicine.

Background: We previously conducted a comprehensive survey of energy metabolism in osteoarthritis (OA), revealing significant reductions of nicotinamide adenine dinucleotide (NAD⁺) levels in OA cartilage. This study aimed to test whether NAD⁺ deficiency present in OA plays a mechanistic role in disease development.

Methods: We conducted integrative analyses across human, murine, and rat OA models to examine NAD⁺ metabolism and its regulatory enzymes. The impact of pharmacological NAD⁺ augmentation (via nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR)) and genetic overexpression of the NAD⁺ biosynthetic enzyme NMN adenosyltransferase (NMNAT1) was tested in surgical and aging-related OA models. Expression and function of the NAD⁺-consuming enzyme poly (ADP-ribose) polymerase 14 (PARP14) were examined via siRNA knockdown in chondrocytes under inflammatory conditions, coupled with metabolic assays and extracellular matrix gene profiling.

Results: NAD⁺ levels were decreased in human and murine OA, accompanied by upregulation of both the NAD⁺ biosynthetic enzyme Nicotinamide phosphoribosyltransferase (NAMPT) and the NAD⁺ consuming enzyme PARP14. While NAMPT expression was elevated, its effect on total NAD⁺ may be offset by increased NAD⁺ consumption or substrate limitation under inflammatory conditions. Treatment with NAD⁺ precursors and transgenic overexpression of NMNAT1 suppressed cartilage disruption during in aging murine and surgical rat model of OA. Increased expression of PARP14 in OA cartilage contributed to NAD⁺ decline and promoted cartilage degeneration.

Conclusions: This study reveals that dysregulated NAD⁺ metabolism, driven by increased PARP14 consumption, constitutes a potential mechanism underlying OA pathogenesis. Our findings support the concept that enhancing NAD⁺ availability via precursors or biosynthetic pathway modulation may offer disease-modifying effects at the molecular and histological level. Further investigation is needed to determine the functional and translational implications of targeting this pathway.

Background: Lafora disease is a rare and fatal form of progressive myoclonus epilepsy that typically manifests in late childhood, presenting with seizures and progressive neurological decline. It is caused by mutations in EPM2A or EPM2B genes, encoding laforin and malin, which form a complex that regulates glycogen metabolism and mitigates cellular stress. Loss of function in either gene leads to the accumulation of Lafora bodies, insoluble polyglucosan aggregates that contribute to neurodegeneration.

Methods: We previously demonstrated the efficacy of gene therapy using intracerebroventricular delivery of rAAV2/9 vectors expressing EPM2A or EPM2B in mouse models of Lafora disease. Building on these findings, we investigated the therapeutic and translational potential of a less invasive approach using intravenous delivery of rAAV2/9P31 vectors, which efficiently cross the blood–brain barrier. Gene delivery was performed at presymptomatic stages in Epm2a^−/− and Epm2b^−/− mice.

Results: Intravenous gene therapy with rAAV2/9P31 vectors carrying EPM2A or EPM2B reversed neuropathological features of the disease, restored neuronal excitability and synaptic plasticity, and effectively prevented Lafora body formation. The therapeutic outcomes were comparable or superior to those achieved with intracerebroventricular administration. Long-term evaluation revealed no evidence of hepatotoxicity or immunogenicity.

Conclusion: Our results support intravenous rAAV2/9P31–mediated gene therapy as a promising, less invasive, and safe treatment strategy for Lafora disease, with strong potential for clinical translation.