Inorganic pyrophosphatase 1: a key player in immune and metabolic reprogramming in ankylosing spondylitis
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Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies
Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic and epigenetic alterations. Enhancer reprogramming has emerged as a pivotal driver of carcinogenesis, with cancer cells often relying on aberrant transcriptional programs. The advent of high-throughput sequencing technologies has provided critical insights into enhancer reprogramming events and their role in malignancy. While targeting enhancers presents a promising therapeutic strategy, significant challenges remain. These include the off-target effects of enhancer-targeting technologies, the complexity and redundancy of enhancer networks, and the dynamic nature of enhancer reprogramming, which may contribute to therapeutic resistance. This review comprehensively encapsulates the structural attributes of enhancers, delineates the mechanisms underlying their dysregulation in malignant transformation, and evaluates the therapeutic opportunities and limitations associated with targeting enhancers in cancer.
Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies
Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.
Trained immunity in type 2 immune responses
Immunological memory of innate immune cells, also termed “trained immunity”, allows for cross-protection against distinct pathogens, but may also drive chronic inflammation. Recent studies have shown that memory responses associated with type 2 immunity do not solely rely on adaptive immune cells, such as T- and B cells, but also involve the innate immune system and epithelial cells. Memory responses have been described for monocytes, macrophages and airway epithelial cells of asthmatic patients as well as for macrophages and group 2 innate lymphoid cells (ILC2) from allergen-sensitized or helminth-infected mice. The metabolic and epigenetic mechanisms that mediate allergen- or helminth-induced reprogramming of innate immune cells are only beginning to be uncovered. Trained immunity has been implicated in helminth-driven immune regulation and allergen-specific immunotherapy, suggesting its exploitation in future therapies. Here, we discuss recent advances and key remaining questions regarding the mechanisms and functions of trained type 2 immunity in infection and inflammation.
Type 2 immunity in allergic diseases
Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.
Nonenzymatic lysine d-lactylation induced by glyoxalase II substrate SLG dampens inflammatory immune responses
Immunometabolism is critical in the regulation of immunity and inflammation; however, the mechanism of preventing aberrant activation-induced immunopathology remains largely unclear. Here, we report that glyoxalase II (GLO2) in the glycolysis branching pathway is specifically downregulated by NF-κB signaling during innate immune activation via tristetraprolin (TTP)-mediated mRNA decay. As a result, its substrate S-D-lactoylglutathione (SLG) accumulates in the cytosol and directly induces d-lactyllysine modification of proteins. This nonenzymatic lactylation by SLG is greatly facilitated by a nearby cysteine residue, as it initially reacts with SLG to form a reversible S-lactylated thiol intermediate, followed by SN-transfer of the lactyl moiety to a proximal lysine. Lactylome profiling identifies 2255 lactylation sites mostly in cytosolic proteins of activated macrophages, and global protein structure analysis suggests that proximity to a cysteine residue determines the susceptibility of lysine to SLG-mediated d-lactylation. Furthermore, lactylation is preferentially enriched in proteins involved in immune activation and inflammatory pathways, and d-lactylation at lysine 310 (K310) of RelA attenuates inflammatory signaling and NF-κB transcriptional activity to restore immune homeostasis. Accordingly, TTP-binding site mutation or overexpression of GLO2 in vivo blocks this feedback lactylation in innate immune cells and promotes inflammation, whereas genetic deficiency or pharmacological inhibition of GLO2 restricts immune activation and attenuates inflammatory immunopathology both in vitro and in vivo. Importantly, dysregulation of the GLO2/SLG/d-lactylation regulatory axis is closely associated with human inflammatory phenotypes. Overall, our findings uncover an immunometabolic feedback loop of SLG-induced nonenzymatic d-lactylation and implicate GLO2 as a promising target for combating clinical inflammatory disorders.
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