Adipose tissue hypertrophy, the local infiltration of immune cells, the increased production of proinflammatory cytokines, the whitening of brown adipose tissue, local hypoxia and angiogenesis disorders occur in obese individuals, which in turn lead to adipose tissue inflammation and promote the occurrence and development of metabolic diseases such as type 2 diabetes (T2DM), atherosclerosis and metabolic dysfunction‑associated steatotic liver disease (MASLD). In recent years, N6‑methyladenine (m6A), the most representative epigenetic modification, has been shown to be significantly altered in individuals with obesity and to participate in the regulation of various metabolic diseases. In the present review, the links between m6A modification and obesity‑related metabolic diseases, such as MASLD and T2DM, from the perspective of adipose tissue inflammation are examined. Additionally, the challenges and prospects associated with targeting m6A in adipose tissue inflammation and metabolic diseases are discussed to provide new ideas for the treatment of these conditions.

Hepatocellular carcinoma (HCC) is a highly malignant cancer closely related to the chronic inflammation induced by persistent liver damage. Various risk factors, including chronic hepatitis B/C virus infections, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease, aflatoxins exposure, and metabolic disorders, contribute to genetic mutations in hepatocytes, leading to sustained cellular damage and apoptosis. These processes foster a chronic inflammatory microenvironment that activates hepatic stellate cells, promotes extracellular matrix deposition, and triggers aberrant regenerative repair, ultimately advancing liver fibrosis, cirrhosis, and HCC. The transition from chronic liver injury to HCC is governed by two interconnected mechanistic layers: initiating triggers-viral infection and hepatocyte death-that provide the substrate for malignant transformation, and modulatory systems that determine the trajectory of this process. Recent studies have revealed that diverse cell types and molecular signaling pathways form an intercellular regulatory network that fosters an inflammatory and carcinogenic microenvironment. This review focuses on three such modulatory systems-the hepatic immune microenvironment, the gut-liver axis, and neuroregulation-and examines how their interplay influences malignant behaviors including cell transformation, proliferation, and apoptosis. We systematically overview the key cellular constituents, fundamental molecular mechanisms, and core signaling pathways governing inflammation-induced hepatocarcinogenesis, and discuss potential therapeutic targets emerging from current research. A deeper understanding of these fundamental pathological mechanisms provides a conceptual framework for elucidating the initiation and progression of HCC. It also offers a theoretical basis for the future development of preventive and targeted therapeutic strategies, although the translation of these mechanistic insights into clinically effective interventions-particularly for cancer prevention-will require rigorous validation in large-scale, prospective human studies.

Semaphorins were initially identified as axon guidance molecules in the nervous system, where they transmit repulsive signals to restrict axonal growth by regulating the dynamics of growth cone cytoskeletal structures. Subsequent studies have demonstrated that semaphorin signaling can restrict the migration of CD8⁺ T cell precursors driven by chemokines, thereby maintaining the corticomedullary structure of the thymus. In recent years, increasing evidence has revealed that semaphorins and their receptors (such as plexins and neuropilins) play critical roles in the lymph node homing and activation of CD8⁺ T cells, as well as in their migration and effector functions within the tumor microenvironment. This review summarizes recent advances in understanding the roles of semaphorins and their receptors in CD8⁺ T cell development, migration, and function, highlighting their potential as targets for cancer immunotherapy.

Metabolic-associated fatty liver disease (MAFLD), the most prevalent chronic hepatic disorder globally, is pathologically characterized by excessive intrahepatic lipid deposition, oxidative stress, and chronic low-grade inflammation. Apolipoprotein A-I binding protein (AIBP), a critical modulator of lipid metabolism, cellular signaling pathways, inflammatory responses, and metabolic homeostasis, has not been thoroughly investigated in the context of MAFLD pathogenesis. In this study, we identified a significant downregulation of AIBP expression in both high-fat diet (HFD)-induced MAFLD murine models and palmitic acid (PA)-treated HepG2 cells. Systemic AIBP deficiency exacerbated metabolic dysregulation and induced profound perturbations in hepatic architecture and function, culminating in aggravated liver injury. This was evidenced by enhanced steatosis, elevated pro-inflammatory cytokine production, and increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Transcriptomic profiling and molecular characterization of AIBP-deficient HepG2 cells corroborated these pathological alterations. Mechanistic investigations revealed that AIBP silencing potentiates hepatic damage through integrin β3 (ITGβ3)-mediated hyperactivation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling cascade. Notably, hepatocyte-specific AIBP overexpression effectively ameliorated these metabolic and inflammatory aberrations. Collectively, our findings establish AIBP as a pivotal hepatoprotective regulator in MAFLD pathogenesis and propose a novel therapeutic paradigm for MAFLD and associated metabolic disorders through targeted AIBP modulation. This study provides compelling evidence for the development of AIBP-centered therapeutic strategies to mitigate MAFLD progression.

Background and Aim The formation of subendothelial macrophage-derived foam cells is a key driver of atherogenesis and contributes to the onset and progression of atherosclerosis (AS). The METTL3 gene, a central mediator of N6-methyladenosine (m6A) RNA methylation, serves as a critical regulatory node at the inflammation-metabolism nexus in immune pathophysiology. Methods and Result This study aimed to investigate the METTL3-mediated regulatory mechanisms in subendothelial macrophage-derived foam cells formation and their association with necrosis and the pro-inflammatory properties of AS lesions. METTL3 expression was significantly higher in human carotid artery plaques compared to non-plaques. Macrophages treated with ox-LDL had an upregulated METTL3 expression, while its knockdown reduced lipid accumulation, foam cell formation, and inflammatory responses in macrophages. Myeloid Mettl3 knockout AS mice exhibited attenuated AS lesions. METTL3 knockdown elevated ABCA1, LXR-α, and ZNF771 expression. Gain- and loss-of-function studies demonstrated that METTL3 modulates lipid accumulation and inflammation partly through the ZNF771/LXR-α/ABCA1 axis. YTHDF2 knockdown increased ZNF771 levels, indicating that METTL3 cooperates with YTHDF2 to suppress ZNF771 expression, thereby inhibiting LXR-α transcription. Macrophage METTL3 exacerbates AS by suppressing cholesterol efflux and amplifying inflammation through YTHDF2-mediated downregulation of ZNF771, which attenuates the LXR-α/ABCA1 axis. Conclusions Our study identifies a novel METTL3-dependent mechanistic link between foam cell pathology and plaque destabilization.

With the development of obese adipose tissue (AT), adipocytes undergo pathological changes from inert energy storage to excessive and active endocrine organs associated with disease hazards. Methyltransferase 3 (METTL3) is an RNA methyltransferase with key roles in AT development, functional maintenance and metabolic homeostasis. Licoisoflavone A (LIC‑A) is a prenylated flavonoid compound derived from licorice, which has anti‑inflammatory, antihypertrophic and antiproliferative activities; however, whether it directly modulates METTL3 expression and affects AT function in obesity remains unknown. In the present study, molecular docking of compounds from the traditional Chinese medicine formula Fangji‑Huangqi Decoction against METTL3, identified 16 top‑ranked candidate molecules. Among these candidates, LIC‑A was identified as a potential upstream regulator of METTL3 and markedly increased METTL3 expression. The effects of TNF‑α and lipopolysaccharide treatments on the inhibition of adipogenesis were successfully recovered by LIC‑A treatment of the adipogenic 3T3‑L1 cells, via the regulation of adipogenic cytokines, as well as the expression of inflammatory factors. These protective effects were similarly abolished by METTL3 knockdown, suggesting that the role of LIC‑A relies on METTL3. Moreover, in vivo data demonstrated that the administration of LIC‑A could notably recover body weight lipid metabolism, insulin resistance and gluconeogenesis in mice with reduced adipose deposition, as well as abate systemic inflammation. The novelty of the present study lies in three aspects: i) LIC‑A was identified as a previously unrecognized upstream positive regulator of METTL3 expression; ii) LIC‑A was demonstrated to alleviate adipokine dysregulation and AT inflammation through a METTL3‑dependent mechanism; and iii) the first in vivo experimental evidence that LIC‑A can improve obesity‑related metabolic disorders by promoting METTL3‑mediated m6A methylation in AT was provided. To the best of our knowledge, this is the first study to link a natural isoflavone compound from licorice to METTL3‑mediated post‑transcriptional regulation in the context of AT dysfunction.

Ketogenic diets, which are characterized by high fat, moderate protein, and very low carbohydrate intake, have attracted increasing interest because of their potential functional relevance to metabolic and neuroimmune regulation. Available evidence suggests that ketogenic diets may modulate inflammatory and immune-related pathways and alter the composition of the gut microbiota. In individuals with type 1 diabetes mellitus, ketogenic dietary approaches have been associated with glycaemic stability, body weight regulation, and potential effects on mood- and cognition-related outcomes. In patients with multiple sclerosis, ketogenic diets may be associated with changes in sleep quality, gut microbial fermentation, muscle-related outcomes, and neuroprotective processes. Evidence from small and observational studies suggests potential associations between ketogenic dietary approaches and quality-of-life– related outcomes in patients with type 1 diabetes mellitus and multiple sclerosis; however, the current findings remain preliminary and are insufficient to establish efficacy and safety.

Crohn’s disease is a chronic inflammatory bowel disease that is closely associated with genetic factors, immune dysregulation and microbial imbalance. Lesions involving the oral cavity and upper gastrointestinal tract constitute a common yet clinically overlooked manifestation of this disease. This article reviews the cellular and molecular mechanisms underlying disease onset and progression, and evaluates the diagnostic performance of various noninvasive and serum biomarkers. It also summarizes multimodal diagnostic approaches and corresponding therapeutic strategies based on current clinical practice. Currently, relevant clinical trials and standardized evaluation criteria remain lacking, largely because of the limited understanding of disease pathogenesis. Therefore, high-quality basic and translational research will be essential to deepen the understanding of this disease and facilitate the development of precision diagnostic and therapeutic strategies.

Diabetic endothelial dysfunction involves inflammation and endothelial-to-mesenchymal transition (EndMT), however, the underlying RNA N6-methyladenosine (m6A) methylation-mediated regulatory mechanisms remain poorly defined. This study investigated high glucose (HG)-induced diabetic EndMT-like phenotype via RNA m6A methylome, transcriptome, and molecular characterization in human aortic endothelial cells (HAECs). Cell proliferation, morphology, and migration assays were performed. Stagnant cell proliferation during HG treatment began to recover after HG withdrawal. HG treatment altered cell morphology to a highly polarized spindle-like shape. HG-treated cells had a significantly lower cell migration speed. Global m6A methylation and METTL3 expression levels were significantly elevated in HG group. In MeRIP-seq analysis, we found 143 significantly differential hypermethylated peaks and 185 hypomethylated peaks, mainly enriched in pathways related to cell morphology and differentiation-typical of EndMT. In RNA-seq analysis, we found 148 significantly upregulated and 38 significantly downregulated genes implicated in various relevant pathways, including the PI3K-Akt signaling pathway. EndMT-related hub genes query confirmed its transcriptional commencement under HG, which was confirmed by upregulation of TGF-β1, Snail, Slug, mesenchymal vimentin (VIM) and smooth muscle actin (α-SMA), and downregulation of vascular endothelial cadherin (VE cadherin) and CD31. EndMT-like phenotype was significantly reversed in sh-METTL3 cells under HG treatment. Intersection analysis of methylation peak-associated genes identified IGF2 as the main METTL3-mediated m6A candidate due to its hypermethylated peak status and significantly upregulated mRNA expression under HG, and most importantly, its enrichment in the top-most enriched pathway-the PI3K-Akt pathway. Finally, we found phosphorylation-mediated activation of PI3K-Akt pathway implication in diabetic EndMT. This study identifies METTL3-mediated m6A modification in diabetic EndMT and vascular endothelial dysfunction.

Large-scale studies indicate a strong relationship between the gut microbiome, type 2 diabetes mellitus (T2DM), and atherosclerotic cardiovascular disease (ASCVD). Here, a higher abundance of the type III secretion system (T3SS) virulence factors of Enterobacteriaceae/Escherichia-Shigella in patients with T2DM-related-ASCVD, which correlates with their atherosclerotic stenosis is reported. Overexpression of T3SS via Citrobacter rodentium (CR) infection in Apoe-/- T2DM mice exacerbated atherosclerotic lesion formation and increased gut permeability. Non-targeted metabolomic and proteomic analysis of mouse serum showed that T3SS caused abnormal glycerophospholipid metabolism in mice. Proteomics, RNA sequencing, and functional analyses showed that T3SS induced ferroptosis in intestinal epithelial cells, partly due to increased expression of ferritin heavy chains (FTH1). This findings first demonstrated that T3SS increases ferroptosis in intestinal epithelial cells, via disrupting the intestinal barrier and upregulation of phosphatidylcholine, thereby exacerbating T2DM-related ASCVD.

Cancer stem cells were prominent responsible for cancer initiation, metastasis, and invasion as well as therapeutic resistance in colorectal cancer (CRC). The extracellular axon guidance factor netrin-1 has been found to be overexpressed in several malignant cancers such as glioma, lung cancers, and colorectal cancer. However, the role of netrin-1 on cancer stemness in CRC remains unveiled. Our study revealed high expression of netrin-1 in colorectal cancer tissues and its ability to promote cancer stemness by interacting with receptors UNC5B and neogenin on murine colorectal cancer cell. Mechanistically, the netrin-1-UNC5B/neogenin axis activates the downstream NF-κB and ERK1/2 signaling pathways, reinforcing the stemness properties of tumor cells, and further exacerbating tumor progression. Clinically, netrin-1 expression associated with poor survival and high CD133 expression in patients with CRC. Taken together, these results suggest that netrin-1 blockade could be a compelling therapeutic strategy to improve the poor outcomes and trigger cancer stemness inhibition in CRC treatment.

Myeloid-derived suppressor cells (MDSCs) play a key role in inhibiting antitumor immunity and helping tumor cells escape from the immune system. Citrullination is a unique posttranslational modification of proteins that has been found to play a role in tumorigenesis and development. We aimed to determine the role of citrullination regulating MDSCs function in tumor bearing hosts. Immunosuppressive function of PMN-MDSCs was examined in coculture with CD8+T cells. Both phenotype and function of MDSCs upon peptidylarginine deiminase 2 (PAD2) knockdown were analyzed in vitro and in vivo. PAD2-mediated STAT3 citrullination was analyzed by immunoprecipitation and immunofluorescence technique. In this study, we found that knockdown of PAD2 can reduce the immunosuppressive function of PMN-MDSCs and Arg-1 expression. PAD2-mediated STAT3 citrullination can promote its transcription to Arg-1. PAD2 knockdown attenuates the protumorigenic ability of PMN-MDSCs in tumor-bearing mice. These findings demonstrate the PAD2, which mediates the citrullination of STAT3, could enhance the immunosuppressive function of PMN-MDSCs by increasing Arg-1 expression and promoting tumor development.

Netrin-1 is a laminin-related protein found to promote proliferation and invasion in multiple types of cancers. Recent studies have identified the function role of netrin-1 in several cancers; however, the influence of netrin-1 in human gastric cancer(GC) remains largely unknown. In this study, we found netrin-1 was upregulated in human GC tissues, where its expression correlated inversely with cancer stage and lymph node metastasis. We detected netrin-1 and its receptor knockdown significantly suppressed GC cells proliferation and invasion, while overexpression netrin-1 reversed these effects. Xenografted analyses using GC cells displayed significantly inhibition of tumor growth and metastasis by netrin-1 depletion. Furthermore, we identified that netrin-1 as a regulator of PI3K/AKT pathway to modulate GC cells proliferation and invasion abilities via its receptor neogenin. Taken together, our findings argued that netrin-1 and its receptor neogenin might act synergistically in promoting GC cells proliferation and invasion through the PI3K/AKT signaling pathway. It is conceivable that netrin-1 could be new therapeutic target to GC therapy.

Many factors, including genetic vulnerability, barrier function, intestinal immune cells, and intestinal microbiota, may combine to affect the occurrence and progression of inflammatory bowel disease (IBD). Through targeting bile acid receptors (BARs), bile acids have been demonstrated to have a range of regulatory effects on intestinal immune responses in recent decades. As the basis of intestinal immunity, macrophages play an indispensable role in intestinal homeostasis. BARs connect the intestinal microbiota with immune cells, significantly impacting IBD. This review focuses on the role of bile acids in regulating the differentiation and function of intestinal macrophages in IBD.

Macrophage metabolic reprogramming refers to the process by which macrophages adjust their physiological pathways to meet survival and functional demands in different immune microenvironments. This involves a range of metabolic pathways, including glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and cholesterol transport. By modulating the expression and activity of key enzymes and molecules within these pathways, macrophages can make the transition between pro- and anti-inflammatory phenotypes, thereby linking metabolic reprogramming to inflammatory responses and the progression of several diseases, such as atherosclerosis, inflammatory bowel disease (IBD), and acute lung injury (ALI). N6-methyladenosine (m6A) modification has emerged as a critical regulatory mechanism during macrophage metabolic reprogramming, broadly affecting RNA stability, translation, and degradation. Therapeutic strategies targeting m6A modification can regulate the onset of metabolic diseases by influencing macrophage metabolic changes, for instance, small molecule inhibitors of methyltransferase-like 3 (METTL3) can affect glucose metabolism and inhibit IBD. This review systematically explores recent findings on the role and molecular mechanisms of m6A modification during macrophage metabolic reprogramming in human diseases and animal models, underscoring its potential as a therapeutic target for metabolic diseases.

Macrophages are multifunctional immune cells distributed throughout the whole body, and they have functions in antigen presentation, phagocytosis, killing, and immune regulation. As the most widely studied molecule in the netrin family, netrin-1 plays a key role in neuronal navigation, angiogenesis, and cell survival. Macrophage-derived netrin-1 not only regulates neurovascular regeneration through ligand–receptor binding but also influences macrophage phenotypes by modulating polarization, thereby achieving the purpose of promoting or repairing disease damage. In this review, we will summarize the recent research advances on the role of macrophage-derived netrin-1 and its receptors in a variety of inflammatory diseases and cancers.

Background Atherosclerosis (AS) is the most prevalent cardiovascular disease and remains the major contributor to death and mortality globally. Leonurine (LEO) is a unique alkaloid compound with protective effects on the cardiovascular system. However, the exact mechanisms underlying its cardiovascular-protecting action are still not fully elucidated. The methyltransferase 3 (METTL3), the catalytic core of the N6-methyladenosine modification (m6A) methyltransferase complex, has been shown to inhibit autophagy and exacerbate the process of AS via regulation of m6A modification of mRNA. Purpose We aimed to determine whether the inhibited effect of LEO on AS is related to METTL3-mediated AKT1S1 stability. Methods The apolipoprotein E (ApoE) knockout mice was subjected to a high-fat diet (HFD), and THP-1 derived macrophages was exposed to oxidized low-density lipoprotein (ox-LDL), to establish the animal and cellular models of AS, respectively. Results We found that LEO effectively improved AS and reduced the plaque area and inflammation via diminishing macrophage lipid accumulation and remodeling the lipid metabolism profile. LEO activated ox-LDL-induced macrophage autophagy, enhancing lipid metabolism decrease, according to the lipidomic and molecular biology analyses. Additionally, LEO caused a marked increase in autophagy marker levels in mouse models with advanced AS. Furthermore, we found that LEO reactivated autophagy and reversed lipid accumulation by suppressing METTL3 expression. The m6A-seq from ox-LDL-induced macrophages showed that a total of five autophagy-related mRNA transcripts (AKT1S1, AKT1, RB1CC1, CFLAR, and MTMR4) were altered, and AKT1S1 was significantly upregulated by LEO. Mechanistically, LEO-mediated regulation of METTL3 decreased AKT1S1 expression by attenuating its mRNA stability. Silencing AKT1S1 inhibited LEO-METTL3 axis-mediated autophagy and enhanced lipid accumulation in ox-LDL-induced macrophages. Conclusion The study first revealed that LEO exerts anti-atherosclerotic effect by activating METTL3-mediated macrophage autophagy in vivo and in vitro. The mechanism of LEO was further found to be the enhancement of METTL3-mediated AKT1S1 stability to activate autophagy thereby reducing lipid accumulation. This study provides a new perspective of natural medicines on the treatment of AS via an epigenetic manner.

Colitis-associated colorectal cancer has been a hot topic in public health issues worldwide. Numerous studies have demonstrated the significance of myeloid-derived suppressor cells (MDSCs) in the progression of this ailment, but the specific mechanism of their role in the transformation of inflammation to cancer is unclear, and potential therapies targeting MDSC are also unclear. This paper outlines the possible involvement of MDSC to the development of colitis-associated colorectal cancer. It also explores the immune and other relevant roles played by MDSC, and collates relevant targeted therapies against MDSC. In addition, current targeted therapies for colorectal cancer are analyzed and summarized.

Epithelial-to- mesenchymal transition (EMT) contributes to tumor initiation, invasion, and metastasis as well as chemotherapy failure. Recently, Lengrand and her colleagues reported that netrin-1 blockade by administration of NP137 decreased the proportion of EMT tumor cells in skin squamous cell carcinoma, decreased the number of metastases, and increased the sensitivity of tumor cells to chemotherapy. Meanwhile, in another study, Cassier et al also demonstrated that NP137 can inhibit tumor growth and EMT in mouse models and in a first-in- human trial of endometrial carcinomas. These results indicate the importance of anti-netrin- 1 strategy for targeting EMT in cancer.