CD36 affects lipid metabolism and is involved in the development of myocardial infarction (MI). O-GlcNAcylation is a promising therapeutic target for myocardial ischemia-reperfusion (I/R) injury. This study aimed to investigate the effects of CD36 on myocardial I/R injury and its O-GlcNAcylation. H9C2 cardiomyocytes were induced by hypoxia/reoxygenation (H/R), and phenotypes were evaluated using cell counting kit-8, EdU assay, flow cytometry, and TUNEL assay. The O-GlcNAcylation was evaluated by immunoprecipitation, immunoblotting, and cycloheximide chase assay. The role of CD36 in vivo was analyzed by TTC staining and TUNEL assay. The results showed that CD36 protein levels were downregulated in I/R rats and H/R-induced H9C2 cells. OGT and O-GlcNAcylation levels were decreased by H/R. Overexpression of CD36 or OGT promoted cell proliferation and inhibited apoptosis of H/R-treated cells. Moreover, OGT facilitated the O-GlcNAcylation of CD36 at S195 site and enhanced CD36 protein stability. Knockdown of CD36 abrogated the effects of cellular behaviors caused by OGT, and CD36 mutation at S195 site reversed the promotion of proliferation and lipid uptake and the inhibition of apoptosis induced by wild-type CD36. Additionally, overexpression of CD36 attenuated infarction and apoptosis in the myocardium of rats. In conclusion, OGT-mediated O-GlcNAcylation of CD36 attenuates myocardial I/R injury through promoting the proliferation and inhibiting apoptosis of cardiomyocytes. The findings suggest that targeting CD36 O-GlcNAcylation may be a promising therapy for MI.

CD36, a transmembrane glycoprotein, which is involved in various cellular functions, including lipid metabolism, inflammation, and tumor initiation and progression, has been considered as an important therapeutic target of tumors. However, the lack of effective imaging methods for non-invasive monitoring of CD36 expression and assessing the efficacy of CD36-targeted therapies limits the clinical application of CD36-targeted therapeutic drugs. To address this issue, we designed and synthesized two novel CD36-targeted radiotracers, and evaluated their biological properties and imaging performance, in order to select the more effective candidate for potential application in monitoring the CD36 expression and assessing the therapeutic efficacy.

The chelator NOTA was conjugated to both linear and cyclic peptides via a bioconjugation approach, yielding the linear peptide conjugate ZL01 and the cyclic peptide conjugate ZL02. Their structures were confirmed using HRMS. The solutions of peptide conjugates (ZL01 and ZL02) were mixed with a [68Ga]GaCl₃ solution to obtain the radiotracers, and the radiochemical purity of both radiotracers was determined by radio-HPLC. Non-radioactive [natGa]Ga-ZL01 and [natGa]Ga-ZL02 were used to confirm [68Ga]Ga-ZL01 and [68Ga]Ga-ZL02. The radiochemical and biological properties were evaluated, including in vitro stability, hydrophilicity, binding affinity, pharmacokinetics, micro PET/CT imaging, and biodistribution.

[68Ga]Ga-ZL01 and [68Ga]Ga-ZL02 were obtained with radiochemical purity over 95 %. Both radiotracers demonstrated hydrophilic character, and good stability in PBS and human serum. The blood clearance of [68Ga]Ga-ZL01 and [68Ga]Ga-ZL02 (half-life) was measured at 17.8 min and 21.6 min, respectively. [natGa]Ga-ZL01 and [natGa]Ga-ZL02 exhibited high binding affinities to U87MG cells, with inhibition constant (Ki) of 1.59 ± 0.35 nM for [natGa]Ga-ZL01 and 1.12 ± 0.44 nM for [natGa]Ga-ZL02, respectively. Micro PET/CT imaging and biodistribution study revealed [68Ga]Ga-ZL02 had superior tumor-to-background ratio and prolonged tumor retention, highlighting its potential as a promising candidate for clinical translation.

In this study, two CD36-targeted radiotracers ([68Ga]Ga-ZL01 and [68Ga]Ga-ZL02) were developed and evaluated. 68Ga-labeled cyclic peptide [68Ga]Ga-ZL02 demonstrated superior tumor-to-background ratio and prolonged tumor retention time, making it a promising radiotracer for monitoring the CD36 expression and assessing the therapeutical efficacy.

Pediatric solid tumors represent a significant subset of childhood cancers, accounting for approximately 60% of new diagnoses. Despite advancements in therapeutic strategies, survival rates remain markedly disparate between high-income and resource-limited settings, underscoring the urgent need for novel and effective treatments. Lipid metabolic reprogramming is a fundamental hallmark of cancer, driving tumor progression, therapeutic resistance, and immune evasion through enhanced fatty acid uptake, increased de novo lipid synthesis, and activated fatty acid β-oxidation (FAO). Ubiquitination, a dynamic post-translational modification mediated by the ubiquitin-proteasome system (UPS), plays a crucial role in regulating lipid metabolism by modulating the stability and activity of key metabolic enzymes and transporters involved in cholesterol and fatty acid pathways. This review comprehensively examines the complex interplay between ubiquitination and lipid metabolic reprogramming in pediatric solid tumors. It delineates the mechanisms by which ubiquitination influences cholesterol biosynthesis, uptake, efflux, and fatty acid synthesis and oxidation, thereby facilitating tumor growth and survival. Furthermore, the review identifies potential UPS-mediated therapeutic targets and explores the feasibility of integrating ubiquitination-based strategies with existing treatments. By targeting the UPS to disrupt lipid metabolism pathways, novel therapeutic avenues may emerge to enhance treatment efficacy and overcome resistance in pediatric oncology. This synthesis of current knowledge aims to provide a foundation for the development of innovative, precision medicine approaches to improve clinical outcomes for children afflicted with solid tumors.

Peimine is a isosteroidal alkaloid with multiple biological activities and has gained widespread clinical applications. This study was designed to investigate the effects of peimine (PM) on breast cancer (BC) and the underlying mechanism. Cell counting kit-8, EdU and transwell migration assays were performed to assess the cell viability, proliferation, and migration of MCF-7 and MDA-MB-231 cells. The interaction between USP41 and O-linked N-acetylglucosamine transferase (OGT) was evaluated by co-immunoprecipitation assay. A xenograft mouse model was established. Results showed that the cell viability of MCF-7 and MDA-MB-231 cells was decreased with the increasing concentration of PM, and the concentration of 20 μM was chosen for followed experiments. Besides, PM suppressed the proliferation and migration of MCF-7 and MDA-MB-231 cells. Moreover, PM treatment decreased the O-linked N-acetylglucosaminylation (O-GlcNAcylation) and OGT protein levels in MCF-7 and MDA-MB-231 cells. Mechanically, USP41 interacted with OGT in MDA-MB-231 cells. Overexpression of OGT enhanced the protein stability of USP41. Final rescue results demonstrated that overexpressing OGT or USP41 reversed the decreases of cell viability, proliferation, and migration in PM-treated MCF-7 and MDA-MB-231 cells; while OGT or USP41 knockout showed opposite results. Animal studies showed that PM treatment inhibited the tumor growth. In summary, PM inhibited cell viability, proliferation, and migration of BC by regulating the O-GlcNAcylation of USP41.

Brain metastases are the most commonly diagnosed type of central nervous system tumor, yet the mechanisms of their occurrence are still widely unknown. Lung cancer, breast cancer, and melanoma are the most common etiologies, but renal and colorectal cancers have also been described as metastasizing to the brain. Regardless of their origin, there are common mechanisms for progression to all types of brain metastases, such as the creation of a suitable tumor microenvironment in the brain, priming of tumor cells, adaptations to survive spreading in lymphatic and blood vessels, and development of mechanisms to penetrate the blood-brain barrier. However, there are complex genetic and molecular interactions that are specific to every type of primary tumor, making the understanding of the metastatic progression of tumors to the brain a challenging field of study. In this review, we aim to summarize current knowledge on the pathophysiology of brain metastases, from specific genetic characteristics of commonly metastatic tumors to the molecular and cellular mechanisms involved in progression to the central nervous system. We also briefly discuss current challenges in targeted therapies for brain metastases and how there is still a gap in knowledge that needs to be overcome to improve patient outcomes.

In the realm of oncology, the tumor microenvironment (TME)-comprising extracellular matrix components, immune cells, fibroblasts, and endothelial cells-plays a pivotal role in tumorigenesis, progression, and response to therapeutic interventions. Initially, the TME exhibits tumor-suppressive properties that can inhibit malignant transformation. However, as the tumor progresses, various factors induce immune tolerance, resulting in TME behaving in a state that promotes tumor growth and metastasis in later stages. This state of immunosuppression is crucial as it enables TME to change from a role of killing tumor cells to a role of promoting tumor progression. Gastric cancer is a common malignant tumor of the gastrointestinal tract with an alarmingly high mortality rate. While chemotherapy has historically been the cornerstone of treatment, its efficacy in prolonging survival remains limited. The emergence of immunotherapy has opened new therapeutic pathways, yet the challenge of immune tolerance driven by the gastric cancer microenvironment complicates these efforts. This review aims to elucidate the intricate role of the TME in mediating immune tolerance in gastric cancer and to spotlight innovative strategies and clinical trials designed to enhance the efficacy of immunotherapeutic approaches. By providing a comprehensive theoretical framework, this review seeks to advance the understanding and application of immunotherapy in the treatment of gastric cancer, ultimately contributing to improved patient outcomes.

Metabolomics and 16S rDNA sequencing have shown great potential in elucidating complex mechanisms associated with diseases. Currently, there is little research on the omics of gastric cancer and it lacks effective biomarkers.

Based on plasma metabolomics and 16S rDNA sequencing to evaluate the changes in metabolites and fecal microbiota of advanced gastric cancer.

Firstly, plasma metabolomics was used to screen for differential metabolites and metabolic pathways in gastric cancer. Then, 16S rDNA sequencing was performed on fecal samples to study the differential intestinal microbiota in gastric cancer patients. Finally, conduct a correlation analysis between them.

A total of 152 differential metabolites were identified, and we screened 10 of them. All metabolites were enriched into 42 differential metabolic pathways, of which 13 have P values less than 0.05. 16S rDNA sequencing showed significant differences in 4 microbial communities at the phylum level. There are significant differences in 23 communities at the genus level. We focus on Lactobacillales, Lactobacillus, Streptococcus, Veillonella, Bacilli and Megasphaera. Correlation analysis shows that the intestinal microbiota and plasma metabolites jointly affect the occurrence and development of gastric cancer.

For the first time, we comprehensively used plasma metabolomics and 16S rDNA sequencing to reveal the changes and correlations between metabolites and intestinal microbiota in advanced gastric cancer. We have discovered new potential biomarkers for gastric cancer. This deepens our understanding of the physiological and pathological mechanisms of advanced gastric cancer and helps to improve the diagnosis and treatment of advanced gastric cancer.

Dysregulated lipid metabolism within the tumor microenvironment (TME) is a critical hallmark of cancer progression, with lipids serving as a major energy source for tumor cells. Beyond their role in cell membrane synthesis, lipids also provide essential substrates for biomolecule production and activate signaling pathways that regulate various cellular processes. Aberrant lipid metabolism impacts not only function but also alters the behavior of immune and stromal cells within the TME. CD36, a key lipid transporter, plays a crucial role in regulating fatty acid sensing and lipid metabolism, and its dysregulated expression has been associated with poor prognosis in several cancers. Studies have demonstrated that elevated CD 36 expression in the TME is closely linked to abnormal lipid metabolism, promoting tumor growth, migration, and metastasis. In recent years, significant progress has been made in developing CD36-targeted therapies, including small-molecule inhibitors, antibodies, and nanoparticle-based drugs, with many entering experimental or preclinical stages. This review comprehensively summarizes the latest advances in understanding the role of CD36 in the TME, focusing on its metabolic regulatory mechanisms in tumor cells, immune cells, and stromal cells. Additionally, it highlights the contribution of CD36 to immune evasion, drug resistance, and cancer stem cell maintenance while discussing several therapeutic strategies targeting CD36, including novel therapies currently in clinical trials. By exploring the therapeutic potential of CD36, this review provides critical insights for the future development of CD36-targeted cancer therapies.

We aim to identify molecular clusters related to O-GlcNAcylation and establish a novel scoring system for predicting prognosis and immunotherapy efficacy in patients with gastric cancer (GC). The transcriptomic and clinical data are obtained from XENA-UCSC and GEO databases. The O-GlcNAcylation-related genes are obtained from the GSEA database. Consensus clustering analysis is employed to identify O-GlcNAcylation-related molecular clusters, and principal component analysis (PCA) is utilized to develop a novel prognostic scoring system for predicting GC outcomes and immunotherapy efficacy. The prognostic accuracy of the scoring system is assessed across five real-world cohorts. The biological function of actin alpha 2, smooth muscle (ACTA2) in GC is determined through experimental verification. Using 34 O-GlcNAcylation-related genes associated with prognosis in GC patients, these individuals are divided into two distinct subgroups characterized by different outcomes, tumor microenvironment profiles, and clinical case characteristics. The DEGs between the two subgroups are subsequently used to further divide the GC patients into two subgroups by consensus cluster analysis. PCA is used to construct a prognostic scoring system, which reveal that patients in the low-score subgroup have a better prognosis and greater benefit from immunotherapy. The accuracy of the scoring system is confirmed through validation in a cohort of patients receiving immunotherapy in the real world. ACTA2 promotes proliferation and inhibits apoptosis in GC cells. These findings suggest that we successfully establish molecular clusters associated with O-GlcNAcylation and develop a scoring system that demonstrates strong performance in predicting the prognosis of patients with GC and the effect of immunotherapy interventions.

Despite the development of cancer biomarkers and targeted therapies, most cancer patients do not have a specific biomarker directly associated with effective treatment options. We have developed VT1021 that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). Our studies identified CD36 and CD47 as dual biomarkers that can be used as patient stratifying tools and prognostic biomarkers for VT1021 treatment.

Cluster of differentiation 36 (CD36) is a multiligand receptor with important roles in lipid metabolism, angiogenesis and innate immunity, and its diverse effects may depend on the binding of specific ligands in different contexts. CD36 is expressed not only on immune cells in the tumor microenvironment (TME) but also on some hematopoietic cells. CD36 is associated with the growth, metastasis and drug resistance in some hematologic tumors, such as leukemia, lymphoma and myelodysplastic syndrome. Currently, some targeted therapeutic agents against CD36 have been developed, such as anti-CD36 antibodies, CD36 antagonists (small molecules) and CD36 expression inhibitors. This paper not only innovatively addresses the role of CD36 in some hematopoietic cells, such as erythrocytes, hematopoietic stem cells and platelets, but also pays special attention to the role of CD36 in the development of hematologic tumors, and suggests that CD36 may be a potential cancer therapeutic target in hematologic tumors.

Lipid metabolism reprogramming has emerged as a hallmark of malignant tumors. Lipids represent a complex group of biomolecules that not only compose the essential components of biological membranes and act as an energy source, but also function as messengers to integrate various signaling pathways. In tumor cells, de novo lipogenesis plays a crucial role in acquiring lipids to meet the demands of rapid growth. Increasing evidence has suggested that dysregulated lipid metabolism serves as a driver of cancer progression. Posttranslational modifications (PTMs), which occurs in most eukaryotic proteins throughout their lifetimes, affect the activity, abundance, function, localization, and interactions of target proteins. PTMs of crucial molecules are potential intervention sites and are emerging as promising strategies for the cancer treatment. However, there is limited information available regarding the PTMs that occur in cancer lipid metabolism and the potential treatment strategies associated with these PTMs. Herein, we summarize current knowledge of the roles and regulatory mechanisms of PTMs in lipid metabolism. Understanding the roles of PTMs in lipid metabolism in cancer could provide valuable insights into tumorigenesis and progression. Moreover, targeting PTMs in cancer lipid metabolism might represent a promising novel therapeutic strategy.

Energy metabolic reprogramming is frequently observed during tumor progression as tumor cells necessitate adequate energy production for rapid proliferation. Although current medical research shows promising prospects in studying the characteristics of tumor energy metabolism and developing anti-tumor drugs targeting energy metabolism, there is a lack of systematic compendiums and comprehensive reviews in this field. The objective of this study is to conduct a systematic review on the characteristics of tumor cells' energy metabolism, with a specific focus on comparing abnormalities between tumor and normal cells, as well as summarizing potential targets for tumor therapy. Additionally, this review also elucidates the aberrant mechanisms underlying four major energy metabolic pathways (glucose, lipid, glutamine, and mitochondria-dependent) during carcinogenesis and tumor progression. Through the utilization of graphical representations, we have identified anomalies in crucial energy metabolism pathways, encompassing transporter proteins (glucose transporter, CD36, and ASCT2), signaling molecules (Ras, AMPK, and PTEN), as well as transcription factors (Myc, HIF-1α, CREB-1, and p53). The key molecules responsible for aberrant energy metabolism in tumors may serve as potential targets for cancer therapy. Therefore, this review provides an overview of the distinct energy-generating pathways within tumor cells, laying the groundwork for developing innovative strategies for precise cancer treatment.

Gastric adenocarcinoma (GA) is a significant global health issue with poor prognosis, despite advancements in treatment. Although molecular classifications, such as The Cancer Genome Atlas (TCGA), provide valuable insights, their clinical utility remains limited. We performed a multi-layered functional analysis using TCGA RNA sequencing data to better define molecular subtypes and explore therapeutic implications. We reanalyzed TCGA RNA-seq data from 142 GA patients with localized disease who received adjuvant chemotherapy. Our approach included probabilistic graphical models and recurrent sparse k-means/consensus cluster algorithms for layer-based analysis. Our findings revealed survival differences among TCGA groups, with the GS subtype showing the poorest prognosis. We identified twelve functional nodes and seven biological layers, each with distinct functions. The combined molecular layer (CML) classification identified three prognostic groups that align with TCGA subtypes. CML2 (GS-like) displayed gene expression related to lipid metabolism, correlating with worse survival. Transcriptomic heterogeneity within the CIN subtype revealed clusters tied to proteolysis and lipid metabolism. We identified a subset of CIN tumors with profiles similar to MSI, termed CIN-MSI-like. Claudin-18, a key gene in proteolysis, was overexpressed across TCGA subtypes, suggesting it is a potential therapeutic target. Our study advances GA biology, enabling refined stratification and personalized treatment. Further studies are needed to translate these findings into clinical practice.

The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is a common and important post-translational modification (PTM) linking O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues in proteins. Extensive research indicates its impact on target protein stability, activity, and interactions. O-linked N-acetylglucosamine transferase (OGT) is a critical enzyme that catalyzes O-GlcNAc modification, responsible for adding O-GlcNAc to proteins. OGT and O-GlcNAcylation are overexpressed in many tumors and closely associated with tumor growth, invasion, metabolism, drug resistance, and immune evasion. This review delineates the biochemical functions of OGT and summarizes its effects and mechanisms in tumors. Targeting OGT presents a promising novel approach for treating human malignancies.

Based on current knowledge, hepatocellular carcinoma (HCC) is a condition with numerous etiologies and risk factors. However, the pathogenesis of HCC remains unclear.

To investigate the roles of senegenin and O-GlcNAcylation in the growth and metastasis of HCC.

The levels of O-linked N-acetylglucosamine transferase (OGT) and O-GlcNAcylation in HCC cells and tissues were detected using western blot analysis. The effects of senegenin and O-GlcNAcylation on the proliferation of HCC cells were investigated in vitro using cell counting kit-8 and clonogenic assays. The potential effects of senegenin and O-GlcNAcylation on HCC metastasis were examined using the transwell migration assay. O-GlcNAcylation levels were altered via drug treatment and lentiviral infection, and western blot analysis was used to detect proteins involved in various pathways.

Western blot analysis revealed that OGT and O-GlcNAcylation levels were significantly elevated in HCC tissues and cells. O-GlcNAcylation levels in HCC cells were significantly altered by drug treatment and lentiviral infection. An increase in the glycosylation level was linked to enhanced proliferation, invasiveness, clonogenicity, and metastatic potential of cancer cells. O-GlcNAcylation induced by senegenin was found to slow the proliferation and migration of HCC cells. The levels of proteins involved in nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, which are associated with endoplasmic reticulum stress, were altered.

Senegenin lowers O-GlcNAcylation levels, decreases OGT expression, and inhibits cancer cell growth and metastasis by regulating proteins involved in NF-κB and JNK pathways.

Gastric cancer is a remarkably heterogeneous tumor. Despite some advances in the diagnosis and treatment of gastric cancer in recent years, the precise treatment and curative outcomes remain unsatisfactory. Poor prognosis continues to pose a major challenge in gastric cancer. Therefore, it is imperative to identify effective targets to improve the treatment and prognosis of gastric cancer patients. It should be noted that glycosylation, a novel form of posttranslational modification, is a process capable of regulating protein function and influencing cellular activities. Currently, numerous studies have shown that glycosylation plays vital roles in the occurrence and progression of gastric cancer. As crucial enzymes that regulate glycan synthesis in glycosylation processes, glycosyltransferases are potential targets for treating GC. Hence, investigating the regulation of glycosyltransferases and the expression of associated proteins in gastric cancer cells is highly important. In this review, the related glycosyltransferases and their related signaling pathways in gastric cancer, as well as the existing inhibitors of glycosyltransferases, provide more possibilities for targeted therapies for gastric cancer.

Hepatocellular carcinoma (HCC) presents significant challenges in treatment and prognosis because of its aggressive nature and high metastatic potential. This study aims to investigate the role of the hexosamine biosynthesis pathway (HBP) and its association with HCC progression and prognosis. We identified SPP1 and FOXM1 as hub genes within the HBP pathway, showing their correlation with poor prognosis and late-stage progression. In addition, the analysis uncovered the complex participation of the HBP pathway in nutrients and oxygen reactions, PI3K-AKT signaling, AMPK activation, and angiogenesis regulation. The disruption of these pathways is pivotal in influencing the growth and progression of HCC. Targeting the HBP presents a promising therapeutic approach to modulate the tumor microenvironment, thereby enhancing the efficacy of immunotherapy. In addition, FOXM1 was identified as the HBP pathway regulator, influencing cellular O-GlcNAcylation level and VEGF secretion, thereby promoting angiogenesis in HCC. Inhibition of O-GlcNAcylation significantly hindered angiogenesis, which is suggested as a potential avenue for therapeutic intervention. Our research demonstrates the practicality of using the HBP-related gene as a prognostic marker in liver cancer patients and suggests targeting FOXM1 as a novel avenue for personalized therapy.

The fatty acid receptor CD36 is expressed on various malignant cells and is suggested to contribute to tumor progression. CD36 is also expressed by several immune cells and involved in immune responses and may be a potential target in cancer immunotherapy. In this study, we investigated whether the selective inhibition of CD36 can inhibit tumor progression and facilitate an antitumor immune response in oral squamous carcinoma cells (OSCCs). We assessed the effects of sulfosuccinimidyl oleate sodium (SSO), a CD36 inhibitor, on the proliferation apoptosis and alteration in tumor cell surface expression levels of immune accessory molecules in vitro. We also assessed whether SSO-treated OSCCs could promote a T cell response via a Mixed Lymphocyte Reaction (MLR) assay. We also investigated the direct antitumor effects and immunomodulatory effects of SSO using a mouse oral cancer OSCC model. SSO treatment significantly inhibited OSCC proliferation, increased apoptotic cell death, and upregulated the cell surface expression of several immune accessory molecules, including CD83, MHC-Class II, and PD-L1. SSO-treated OSCCs augmented T cell proliferation following MLR. In vivo SSO administration significantly attenuated mouse tumor growth with an increased proportion of immune cells, including CD4+ T, CD8+ T, and dendritic cells; it also decreased the proportion of immune suppressive cells, such as myeloid-derived suppressor and regulatory T cells. These results suggest that the selective inhibition of CD36 can induce direct and indirect antitumor effects by facilitating host antitumor immune responses in OSCCs.

The tumor microenvironment (TME) consists of tumor cells, non-tumor cells, extracellular matrix, and signaling molecules, which can contribute to tumor initiation, progression, and therapy resistance. In response to starvation, hypoxia, and drug treatments, tumor cells undergo a variety of deleterious endogenous stresses, such as hypoxia, DNA damage, and oxidative stress. In this context, to survive the difficult situation, tumor cells evolve multiple conserved adaptive responses, including metabolic reprogramming, DNA damage checkpoints, homologous recombination, up-regulated antioxidant pathways, and activated unfolded protein responses. In the last decades, the protein O-GlcNAcylation has emerged as a crucial causative link between glucose metabolism and tumor progression. Here, we discuss the relevant pathways that regulate the above responses. These pathways are adaptive adjustments induced by endogenous stresses in cells. In addition, we systematically discuss the role of O-GlcNAcylation-regulated stress-induced adaptive response pathways (SARPs) in TME remodeling, tumor progression, and treatment resistance. We also emphasize targeting O-GlcNAcylation through compounds that modulate OGT or OGA activity to inhibit tumor progression. It seems that targeting O-GlcNAcylated proteins to intervene in TME may be a novel approach to improve tumor prognosis.

Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process.

Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation.

We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis.

Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.

SARIFA was very recently introduced as a histomorphological biomarker with strong prognostic power for colorectal, gastric, prostate, and pancreatic cancer. It is characterized by the direct contact between tumor cells and adipocytes due to a lack of stromal reaction. This can be easily evaluated on routinely available H&E-slides with high interobserver agreement. SARIFA also reflects a specific tumor biology driven by metabolic reprogramming. Tumor cells in SARIFA-positive tumors benefit from direct interaction with adipocytes as an external source of lipids. Numerous studies have shown that lipid metabolism is crucial in carcinogenesis and cancer progression. We found that the interaction between tumor cells and adipocytes was not triggered by obesity, as previously assumed. Instead, we believe that this is due to an immunological mechanism. Knowledge about lipid metabolism in cancer from basic experiments can be transferred to develop strategies targeting this reprogramed metabolism.

Nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH), constitute a burgeoning worldwide epidemic with no FDA-approved pharmacotherapies. The multifunctional immunometabolic receptor, fatty acid translocase CD36 (CD36), plays an important role in the progression of hepatic steatosis. O-GlcNAcylation is a crucial posttranslational modification that mediates the distribution and function of CD36, but its involvement in NAFLD remains poorly understood.

O-GlcNAcylation and CD36 expression were evaluated in human liver tissues obtained from NASH patients and normal control. Mice with hepatocyte-specific CD36 knockout were administered adeno-associated viral vectors expressing wild-type CD36 (WT-CD36) or CD36 O-GlcNAcylation site mutants (S468A&T470A-CD36) and were provided with a high-fat/high-cholesterol (HFHC) diet for 3 months. RT-qPCR analysis, immunoblotting, dual-luciferase reporter assays, chromatin immunoprecipitation, and coimmunoprecipitation were performed to explore the mechanisms by which O-GlcNAcylation regulates CD36 expression. Membrane protein extraction, immunofluorescence analysis, site-directed mutagenesis, and fatty acid uptake assays were conducted to elucidate the impact of O-GlcNAcylation on CD36 function.

O-GlcNAcylation and CD36 expression were significantly increased in patients with NASH, mouse models of NASH, and palmitic acid-stimulated hepatocytes. Mechanistically, the increase in O-GlcNAcylation facilitated the transcription of CD36 via the NF-κB signalling pathway and stabilized the CD36 protein by inhibiting its ubiquitination, thereby promoting CD36 expression. On the other hand, O-GlcNAcylation facilitated the membrane localization of CD36, fatty acid uptake, and lipid accumulation. However, site-directed mutagenesis of residues S468 and T470 of CD36 reversed these effects. Furthermore, compared with their WT-CD36 counterparts, HFHC-fed S468A&T470A-CD36 mice exhibited decreases in systemic insulin resistance, steatosis severity, inflammation and fibrosis. Pharmacological inhibition of O-GlcNAcylation and CD36 also mitigated the progression of NASH.

O-GlcNAcylation promotes the progression of NAFLD by upregulating CD36 expression and function. Inhibition of CD36 O-GlcNAcylation protects against NASH, highlighting a potentially effective therapeutic approach for individuals with NASH.

Gastric cancer, the fifth most prevalent cancer worldwide, is often diagnosed in advanced stages with limited treatment options. Examining the tumor microenvironment (TME) and its metabolic reprogramming can provide insights for better diagnosis and treatment. This study investigates the link between TME factors and metabolic activity in gastric cancer using bulk and single-cell RNA-sequencing data. We identified two molecular subtypes in gastric cancer by analyzing the distinct expression patterns of 81 prognostic genes related to the TME and metabolism, which exhibited significant protein-level interactions. The high-risk subtype had increased stromal content, fibroblast and M2 macrophage infiltration, elevated glycosaminoglycans/glycosphingolipids biosynthesis, and fat metabolism, along with advanced clinicopathological features. It also exhibited low mutation rates and microsatellite instability, associating it with the mesenchymal phenotype. In contrast, the low-risk group showed higher tumor content and upregulated protein and sugar metabolism. We identified a 15-gene prognostic signature representing these characteristics, including CPVL, KYNU, CD36, and GPX3, strongly correlated with M2 macrophages, validated through single-cell analysis and an internal cohort. Despite resistance to immunotherapy, the high-risk group showed sensitivity to molecular targeted agents directed at IGF-1R (BMS-754807) and the PI3K-mTOR pathways (AZD8186, AZD8055). We experimentally validated these promising drugs for their inhibitory effects on MKN45 and MKN28 gastric cells. This study unveils the intricate interplay between TME and metabolic pathways in gastric cancer, offering potential for enhanced diagnosis, patient stratification, and personalized treatment. Understanding molecular features in each subtype enriches our comprehension of gastric cancer heterogeneity and potential therapeutic targets.

CD36, a scavenger receptor B2 that is dynamically distributed between cell membranes and organelle membranes, plays a crucial role in regulating lipid metabolism. Abnormal CD36 activity has been linked to a range of metabolic disorders, such as obesity, nonalcoholic fatty liver disease, insulin resistance and cardiovascular disease. CD36 undergoes various modifications, including palmitoylation, glycosylation, and ubiquitination, which greatly affect its binding affinity to various ligands, thereby triggering and influencing various biological effects. In the context of tumors, CD36 interacts with autophagy to jointly regulate tumorigenesis, mainly by influencing the tumor microenvironment. The central role of CD36 in cellular lipid homeostasis and recent molecular insights into CD36 in tumor development indicate the applicability of CD36 as a therapeutic target for cancer treatment. Here, we discuss the diverse posttranslational modifications of CD36 and their respective roles in lipid metabolism. Additionally, we delve into recent research findings on CD36 in tumors, outlining ongoing drug development efforts targeting CD36 and potential strategies for future development and highlighting the interplay between CD36 and autophagy in the context of cancer. Our aim is to provide a comprehensive understanding of the function of CD36 in both physiological and pathological processes, facilitating a more in-depth analysis of cancer progression and a better development and application of CD36-targeting drugs for tumor therapy in the near future.

CD36, a membrane protein widely present in various tissues, is crucial role in regulating energy metabolism. The rise of HCC as a notable outcome of NAFLD is becoming more apparent. Patients with hereditary CD36 deficiency are at increased risk of NAFLD. However, the impact of CD36 deficiency on NAFLD-HCC remains unclear.

Global CD36 knockout mice (CD36KO) and wild type mice (WT) were induced to establish NAFLD-HCC model by N-nitrosodiethylamine (DEN) plus high fat diet (HFD). Transcriptomics was employed to examine genes that were expressed differentially.

Compared to WT mice, CD36KO mice showed more severe HFD-induced liver issues and increased tumor malignancy. The MEK1/2-ERK1/2 pathway activation was detected in the liver tissues of CD36KO mice using RNA sequencing and Western blot analysis.

Systemic loss of CD36 leaded to the advancement of NAFLD to HCC by causing lipid disorders and metabolic inflammation, a process that involves the activation of MAPK signaling pathway. We found that CD36 contributes significantly to the maintenance of metabolic homeostasis in NAFLD-HCC.

The contributions of aberrantly expressed metabolic enzymes to gastric cancer (GC) initiation and progression have been widely appreciated in recent years. Acetyl-CoA acetyltransferase 2 (ACAT2) is one member of the acetyl- CoA thiolase family. Previous studies demonstrated that ACAT2 either promotes or suppresses tumor progression in different conditions. However, the function and mechanisms of ACAT2 in GC remain unknown. We found that the expression of this enzyme was significantly increased in GC tissues compared with normal counterparts, which prompted us to further investigate the roles of this protein in GC biology. In vitro functional studies showed that ACAT2 knockdown markedly halted the proliferation and the motility of GC cells; these functions favoring malignant phenotypes of GC cells were further validated in animal experiments. Mechanistically, ACAT2 depletion significantly reduced the transcription of SETD7, which is a histone methyltransferase and plays critical roles in GC cells. We found that the pro-tumoral functions of ACAT2 were largely dependent on SETD7. Moreover, SETD7 decreased the ubiquitination level of Yes-associated protein 1 (YAP1), thereby protecting YAP1 from proteasome degradation. Increased YAP1 protein expression remarkably activated the YAP1/TAZ-TEAD1 signaling pathway, which further boosted the malignant phenotypes in GC cells. In conclusion, these findings highlight the pro-tumoral functions and molecular underpinnings of ACAT2 in GC cells, and suggest that ACAT2 could be a promising target in GC treatment.

Over the years, pancreatic cancer has experienced a global surge in incidence and mortality rates, largely attributed to the influence of obesity and diabetes mellitus on disease initiation and progression. In this study, we investigated the pathogenesis of pancreatic cancer in mice subjected to a high-fat diet (HFD) and observed an increase in citric acid expenditure. Notably, citrate treatment demonstrates significant efficacy in promoting tumor cell apoptosis, suppressing cell proliferation, and inhibiting tumor growth in vivo. Our investigations revealed that citrate achieved these effects by releasing secreted protein acidic and rich in cysteine (SPARC) proteins, repolarizing M2 macrophages into M1 macrophages, and facilitating tumor cell apoptosis. Overall, our research highlights the critical role of citric acid as a pivotal metabolite in the intricate relationship between obesity and pancreatic cancer. Furthermore, we uncovered the significant metabolic and immune checkpoint function of SPARC in pancreatic cancer, suggesting its potential as both a biomarker and therapeutic target in treating this patient population.

Most gastric cancers arise in the setting of chronic inflammation which alters gland organization, such that acid-pumping parietal cells are lost, and remaining cells undergo metaplastic change in differentiation patterns. From a basic science perspective, recent progress has been made in understanding how atrophy and initial pyloric metaplasia occur. However, pathologists and cancer biologists have long been focused on the development of intestinal metaplasia patterns in this setting. Arguably, much less progress has been made in understanding the mechanisms that lead to the intestinalization seen in chronic atrophic gastritis and pyloric metaplasia. One plausible explanation for this disparity lies in the notable absence of reliable and reproducible small animal models within the field, which would facilitate the investigation of the mechanisms underlying the development of gastric intestinal metaplasia (GIM). This review offers an in-depth exploration of the current state of research in GIM, shedding light on its pivotal role in tumorigenesis. We delve into the histological subtypes of GIM and explore their respective associations with tumor formation. We present the current repertoire of biomarkers utilized to delineate the origins and progression of GIM and provide a comprehensive survey of the available, albeit limited, mouse lines employed for modeling GIM and engage in a discussion regarding potential cell lineages that serve as the origins of GIM. Finally, we expound upon the myriad signaling pathways recognized for their activity in GIM and posit on their potential overlap and interactions that contribute to the ultimate manifestation of the disease phenotype. Through our exhaustive review of the progression from gastric disease to GIM, we aim to establish the groundwork for future research endeavors dedicated to elucidating the etiology of GIM and developing strategies for its prevention and treatment, considering its potential precancerous nature.

Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics.

Metastasis causes most cancer-related deaths, and the role and mechanism of periostin (POSTN) in the metastasis of hepatocellular carcinoma (HCC) remain undiscovered. In this study, DEN and HTVi HCC models were performed in hepatic-specific Postn ablation and Postn knock-in mouse to reveal the role of POSTN in HCC metastasis. Furthermore, POSTN was positively correlated with circulating EPCs level and promoted EPC mobilization and tumour infiltration. POSTN also mediated the crosstalk between HCC and EPCs, which promoted metastasis ability and upregulated CD36 expression in HCC through indirect crosstalk. Chemokine arrays further revealed that hepatic-derived POSTN induced elevated CCL2 expression and secretion in EPCs, and CCL2 promoted prometastatic traits in HCC. Mechanistic studies showed that POSTN upregulated CCL2 expression in EPCs via the αvβ3/ILK/NF-κB pathway. CCL2 further induced CD36 expression via the CCR2/STAT3 pathway by directly binding to the promoter region of CD36. Finally, CD36 was verified to have a prometastatic role in vitro and to be correlated with POSTN expression, metastasis and recurrence in HCC in clinical samples. Our findings revealed that crosstalk between HCC and EPCs is mediated by periostin/CCL2/CD36 signalling which promotes HCC metastasis and emphasizes a potential therapeutic strategy for preventing HCC metastasis.

Abnormal lipid metabolism is known to influence the malignant behavior of gastric cancer. However, the underlying mechanism remains elusive. In this study, we comprehensively analyzed the biological significance of genes involved in lipid metabolism in advanced gastric cancer (AGC).

We obtained gene expression profiles from The Cancer Genome Atlas (TCGA) database for early and advanced gastric cancer samples and performed differential expression analysis to identify specific lipid metabolism-related genes in AGC. We then used consensus cluster analysis to classify AGC patients into molecular subtypes based on lipid metabolism and constructed a diagnostic model using least absolute shrinkage and selection operator- (LASSO-) Cox regression analysis and Gene Set Enrichment Analysis (GSEA). We evaluated the discriminative ability and clinical significance of the model using the Kaplan-Meier (KM) curve, ROC curve, DCA curve, and nomogram. We also estimated immune levels based on immune microenvironment expression, immune checkpoints, and immune cell infiltration and obtained hub genes by weighted gene co-expression network analysis (WGCNA) of differential genes from the two molecular subtypes.

We identified 6 lipid metabolism genes that were associated with the prognosis of AGC and used consistent clustering to classify AGC patients into two subgroups with significantly different overall survival and immune microenvironment. Our risk model successfully classified patients in the training and validation sets into high-risk and low-risk groups. The high-risk score predicted poor prognosis and indicated low degree of immune infiltration. Subgroup analysis showed that the risk model was an independent predictor of prognosis in AGC. Furthermore, our results indicated that most chemotherapeutic agents are more effective for AGC patients in the low-risk group than in the high-risk group, and risk scores for AGC are strongly correlated with drug sensitivity. Finally, we performed qRT-PCR experiments to verify the relevant results.

Our findings suggest that lipid metabolism-related genes play an important role in predicting the prognosis of AGC and regulating immune invasion. These results have important implications for the development of targeted therapies for AGC patients.

CD36 is a transmembrane glycoprotein, located on surface of numerous cell types. This review is aimed to explore regulatory role of CD36 in hematopoiesis beyond fatty acid uptake. CD36 acts as a pattern recognition receptor, regulates cellular fatty acid homeostasis, and negatively monitors angiogenesis. CD36 also mediates free fatty acid transportation to hematopoietic stem cells in response to infections. During normal physiology and pathophysiology, CD36 significantly participates in the activation and metabolic needs of platelets, macrophages, monocytes, T cells, B cells, and dendritic cells. CD36 has shown a unique relationship with Plasmodium falciparum-infected erythrocytes (PfIEs) as a beneficiary for both parasite and host. CD36 actively participates in pathogenesis of various hematological cancers as a significant prognostic biomarker including AML, HL, and NHL. CD36-targeting antibodies, CD36 antagonists (small molecules), and CD36 expression inhibitors/modulators are used to target CD36, depicting its therapeutic potential. Many preclinical studies or clinical trials were performed to assess CD36 as a therapeutic target; some are still under investigation. This review reflects the role of CD36 in hematopoiesis which requires more consideration in future research.

Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo, we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36-/-) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro, A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36-/- mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment.

T-2 toxin causes renal dysfunction with proteinuria and glomerular podocyte damage. This work explores the role of metabolic disorder/reprogramming-mediated epigenetic modification in the progression of T-2 toxin-stimulated podocyte injury. A metabolomics experiment is performed to assess metabolic responses to T-2 toxin infection in human podocytes. Roles of protein O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in regulating T-2 toxin-stimulated podocyte injury in mouse and podocyte models are assessed. O-GlcNAc target proteins are recognized by mass spectrometry and co-immunoprecipitation experiments. Moreover, histone acetylation and autophagy levels are measured. T-2 toxin infection upregulates glucose transporter type 1 (GLUT1) expression and enhances hexosamine biosynthetic pathway in glomerular podocytes, resulting in a significant increase in β-arrestin-1 O-GlcNAcylation. Decreasing β-arrestin-1 or O-GlcNAc transferase (OGT) effectively prevents T-2 toxin-induced renal dysfunction and podocyte injury. Mechanistically, O-GlcNAcylation of β-arrestin-1 stabilizes β-arrestin-1 to activate the mammalian target of rapamycin (mTOR) pathway as well as to inhibit autophagy during podocyte injury by promoting H4K16 acetylation. To sum up, OGT-mediated β-arrestin-1 O-GlcNAcylation is a vital regulator in the development of T-2 toxin-stimulated podocyte injury via activating the mTOR pathway to suppress autophagy. Targeting β-arrestin-1 or OGT can be a potential therapy for T-2 toxin infection-associated glomerular injury, especially podocyte injury.