Gastrointestinal malignancies are a major public health concern worldwide, characterized by high incidence and mortality rates. Despite continuous advancements in existing treatment methods, overall survival rates remain low. Lipid metabolism plays a crucial role in the occurrence, progression, and treatment of gastrointestinal malignancies. Its involvement in the metabolic reprogramming of tumor cells, regulation of the tumor microenvironment, and drug response has become a research hotspot.

This review summarizes current research related to lipid metabolism mechanisms, biomarkers, and therapies in GI cancers, with emphasis on its interaction with the tumor microenvironment.

RNF180 (Ring finger protein 180) is an E3 ubiquitin-protein ligase that promotes polyubiquitination and proteasomal degradation. The study aimed to clarify the clinicopathological significances, signal pathways and molecular mechanisms of RNF180 expression in esophageal cancer.

We analyzed the clinicopathological significances and signal pathways of RNF180 expression in esophageal cancer (EC) through bioinformatics and pathological analysis. We also clarified its effects on aggressiveness and related molecular mechanisms in vitro.

RNF180 mRNA expression was lower in EC than in normal tissues (p < 0.05), opposite for its methylation (p < 0.05). RNF180 mRNA expression was negatively correlated with its promoter methylation, but positively with high histological grading, N stage, and poor prognosis of EC (p < 0.05). RNF180 protein expression was positively associated with T stage, N stage, and TNM stage, but negatively with unfavorable overall survival of EC as an independent factor (p < 0.05). The differential genes of RNF180 can be categorized into olfactory transduction, focal adhesion, vascular smooth muscle contraction, calcium signal pathway, cell adhesion molecules, muscle contraction, ECM receptor interaction, and collagen degradation (p < 0.05). RNF180-related genes can be categorized into gastric acid and insulin section, muscle and cardiomyopathy, glycoprotein binding, collagen and extracellular matrix, fat digestion and diabetes, PPAR signal pathway and peptidase activity. RNF180 overexpression reduced proliferation, migration, invasion and epithelial-mesenchymal transition, and induce mitochondrial apoptosis, and Caspase-1-dependent pyroptosis of EC cells (p < 0.05). RNF180 might induce chemosensitivity by weakening ACC1- and ACLY-mediated lipogenesis via the ubiquitination and proteasomal degradation of ACC1 and ACLY, and lipid droplet assembly.

RNF180 might be considered as a biological marker for aggressive behaviors and poor prognosis in EC and as a molecular target of gene therapy.

Dkk3 is discovered through comparative studies of immortalized cells and their parental counterparts and might inhibit the aggressive phenotypes in malignant cells, demonstrating its tumor-suppressor activity. Here, we explored the clinicopathological significance of Dkk3 expression, the association between Dkk3 expression and immune microenvironment, and Dkk3-related signal pathways in gastric cancer (GC), and discovered the effects of Dkk3 on aggressiveness, chemoresistance and lipid droplet formation with molecular mechanisms investigated. Our data showed that plasma level of Dkk3 was low in GC and Dkk3 expression was negatively correlated with younger age, tumor size, depth of invasion, lymph node metastasis, clinicopathological stage and histological classification of GC. Additionally our study shows DKK3 have a potential impact on GC immunity by regulating immune cell infiltration. Overexpression of wild-type and no-signal peptide Dkk3 inhibited cell proliferation, promoted apoptotic and pyroptotic cell death, and suppressed invasion, migration and epithelial-mesenchymal transition in GC cells. Furthermore, Dkk3 expression promoted chemosensitivity by weakening lipid droplet formation in GC cells. The Dkk3-related pathways included ECM (extracellular matrix)-receptor interactions, ECM constituents and organization, WP miRNA targets in ECM membrane receptors, focal adhesion, cAMP, calcium and integrin signaling pathways, basement membranes, spliceosome activity, mitochondrial oxidative phosphorylation, and ubiquitin-like protein binding. These results indicate that Dkk3 expression may serve as a valuable indicator to evaluate the pathological behaviors and immunotherapy of GC. Additionally, Dkk3 could potentially inhibit the aggressiveness regardless of signal peptide, and alleviate chemoresistance by low lipid droplet formation, making it become a valuable molecular target for gene therapy.

Keratin 80 (KRT80) is a filament protein that makes up one of the major structural fibers of epithelial cells, and involved in cell differentiation and epithelial barrier integrity. Here, KRT80 mRNA expression was found to be higher in esophageal cancer than normal epithelium by RT-PCR and bioinformatics analysis (p < .05), opposite to KRT80 methylation (p < .05). There was a negative relationship between promoter methylation and expression level of KRT80 gene in esophageal cancer (p < .05). KRT80 mRNA expression was positively correlated with the differentiation, infiltration of immune cells, and poor prognosis of esophageal cancer (p < .05). KRT80 mRNA expression was positively linked to no infiltration of immune cells, the short survival time of esophageal cancers (p < .05). The differential genes of KRT80 mRNA were involved in fat digestion and metabolism, peptidase inhibitor, and intermediate filament, desosome, keratinocyte differentiation, epidermis development, keratinization, ECM regulator, complement cascade, metabolism of vitamins and co-factor (p < .05). KRT-80-related genes were classified into endocytosis, cell adhesion molecule binding, cadherin binding, cell-cell junction, cell leading edge, epidermal cell differentiation and development, T cell differentiation and receptor complex, plasma membrane receptor complex, external side of plasma membrane, metabolism of amino acids and catabolism of small molecules, and so forth (p < .05). KRT80 knockdown suppressed anti-apoptosis, anti-pyroptosis, migration, invasion, chemoresistance, and lipogenesis in esophageal cancer cells (p < .05), while ACC1 and ACLY overexpression reversed the inhibitory effects of KRT80 on lipogenesis and chemoresistance. These findings indicated that up-regulated expression of KRT80 might be involved in esophageal carcinogenesis and subsequent progression, aggravate aggressive phenotypes, and induced chemoresistance by lipid droplet assembly and ACC1- and ACLY-mediated lipogenesis.

Along with the growing production and application of silica nanoparticles (SiNPs), increased human exposure and ensuing safety evaluation have progressively attracted concern. Accumulative data evidenced the hepatic injuries upon SiNPs inhalation. Still, the understanding of the hepatic outcomes resulting from SiNPs exposure, and underlying mechanisms are incompletely elucidated. Here, SiNPs of two sizes (60 nm and 300 nm) were applied to investigate their composition- and size-related impacts on livers of ApoE-/- mice via intratracheal instillation. Histopathological and biochemical analysis indicated SiNPs promoted inflammation, lipid deposition and fibrosis in the hepatic tissue, accompanied by increased ALT, AST, TC and TG. Oxidative stress was activated upon SiNPs stimuli, as evidenced by the increased hepatic ROS, MDA and declined GSH/GSSG. Of note, these alterations were more dramatic in SiNPs with a smaller size (SiNPs-60) but the same dosage. LC-MS/MS-based quantitative proteomics unveiled changes in mice liver protein profiles, and filtered out particle composition- or size-related molecules. Interestingly, altered lipid metabolism and oxidative damage served as two critical biological processes. In accordance with correlation analysis and liver disease-targeting prediction, a final of 10 differentially expressed proteins (DEPs) were selected as key potential targets attributable to composition- (4 molecules) and size-related (6 molecules) liver impairments upon SiNPs stimuli. Overall, our study provided strong laboratory evidence for a comprehensive understanding of the harmful biological effects of SiNPs, which was crucial for toxicological evaluation to ensure nanosafety.

Colorectal cancer (CRC) is the third most common malignancy worldwide. It is well known that lipid metabolism reprogramming contributes to the tumor progression. However, the lipid metabolic alterations and potential remodeling mechanism underlying the chemoresistance of CRC remain largely unclear. In this study, we compared the gene expression profiles of chemoresistant versus control CRC cells from the GEO database and identified a key factor, Glycerol-3-phosphate acyltransferase 3 (GPAT3), that promotes lipid droplet (LD) production and confers chemoresistance of CRC. With applying of HPLC-MS and molecular dynamics simulation, we also demonstrated that the activity of lysophosphatidic acid synthesis by GPAT3 was dependent on its acetylation at K316 site. In particular, GPAT3-mediated LD accumulation inhibited immunogenic cell death of tumor, and thus facilitated CD8+ T-cell exhaustion and malignant progression in mouse xenografts and hepatic-metastasis tumors in CRC patients. High GPAT3 expression turned CRC cells into nonimmunogenic cells after (Oxaliplatin) Oxa treatment, which was supported by a decrease in cytotoxic IFN-γ release and CD8+ T-cell exhaustion. In conclusion, these findings revealed the role of GPAT3-associated LD accumulation, which conferred a malignant phenotype (chemoresistance) and regulated the tumor microenvironment of CRC. These results suggest that GPAT3 is a potential target to enhance CRC chemosensitivity and develop novel therapeutic interventions.

Head and neck squamous cell carcinoma (HNSCC) is among the most prevalent cancer worldwide, with the most severe impact on quality of life of patients. Despite the development of multimodal therapeutic approaches, the clinical outcomes of HNSCC are still unsatisfactory, mainly caused by relatively low responsiveness to treatment and severe drug resistance. Metabolic reprogramming is currently considered to play a pivotal role in anticancer therapeutic resistance. This review aimed to define the specific metabolic programs and adaptations in HNSCC therapy resistance. An extensive literature review of HNSCC was conducted via the PubMed including metabolic reprogramming, chemo- or immune-therapy resistance. Glucose metabolism, fatty acid metabolism, and amino acid metabolism are closely related to the malignant biological characteristics of cancer, anti-tumor drug resistance, and adverse clinical results. For HNSCC, pyruvate, lactate and almost all lipid categories are related to the occurrence and maintenance of drug resistance, and targeting amino acid metabolism can prevent tumor development and enhance the response of drug-resistant tumors to anticancer therapy. This review will provide a better understanding of the altered metabolism in therapy resistance of HNSCC and promote the development of new therapeutic strategies against HNSCC, thereby contribute to a more efficacious precision medicine.

FAM64A is a mitogen-induced regulator of the metaphase and anaphase transition. Here, we found that FAM64A messenger RNA (mRNA) and protein expression levels were higher in gastric cancer tissue than in normal mucosa (p < .05). FAM64A methylation was negatively correlated with FAM64A mRNA expression (p < .05). The differentially expressed genes of FAM64A were mainly involved in digestion, potassium transporting or exchanging ATPase, contractile fibers, endopeptidase, and pancreatic secretion (p < .05). The FAM64A-related genes were principally categorized into ubiquitin-mediated proteolysis, cell cycle, chromosome segregation and mitosis, microtubule binding and organization, metabolism of amino acids, cytokine receptors, lipid droplet, central nervous system, and collagen trimer (p < .05). FAM64A protein expression was lower in normal gastric mucosa than intestinal metaplasia, adenoma, and primary cancer (p < .05), negatively correlated with older age, T stage, lymphatic and venous invasion, tumor, node, metastasis stage, and dedifferentiation (p < .05), and associated with a favorable overall survival of gastric cancer patients. FAM64A overexpression promoted proliferation, antiapoptosis, migration, invasion, and epithelial-mesenchymal transition via the EGFR/Akt/mTOR/NF-κB, while the opposite effect was observed for FAM64A knockdown. FAM64A also induced chemoresistance directly or indirectly through lipid droplet formation via ING5. These results suggested that upregulation of FAM64A expression might induce aggressive phenotypes, leading to gastric carcinogenesis and its subsequent progression. Thus, FAM64A could be regarded as a prognosis biomarker and a target for gene therapy.

As a member of the G-protein-coupled receptor 1 family, the G-protein-coupled receptor 176 (GPR176) gene encodes a glycosylated protein made up of 515 amino acids. The current study was performed to evaluate the impact of GPR176 on the clinicopathology and prognosis of oesophageal cancer, as well as uncover its molecular mechanisms.

Bioinformatics and clinical tissue samples were used to detect the expression and clinicopathological significance of GPR176 in oesophageal cancer. The expression, proliferation, migration and invasion, apoptosis and lipid droplet formation of GPR176 gene in oesophageal cancer were performed as phenotypic readouts.

Here, RT-PCR and bioinformatic analyses revealed that GPR176 mRNA expression was significantly higher in oesophageal cancer than in normal mucosa (p < 0.05). GPR176 mRNA expression was associated with low weight and BMI, low T stage, low N and clinicopathological stage, low histological grade and favourable clinical outcome of oesophageal cancer (p < 0.05). The differential genes of GPR176 mRNA were involved in protein digestion and absorption, extracellular matrix constituent, endoplasmic reticulum lumen, among others (p < 0.05). GPR176-related genes were classified as being involved in oxidoreductase activity, actin and myosin complexes, lipid localisation and transport, among others (p < 0.05). GPR176 knockdown suppressed proliferation, anti-apoptotic and anti-pyroptotic properties, migration, invasion, chemoresistance and lipid droplet formation in oesophageal cancer cells (p < 0.05), while ACC1 and ACLY overexpression reversed the inhibitory effects of GPR176 silencing on lipid droplet formation and chemoresistance.

These findings indicated that upregulated expression of GPR176 might be involved in oesophageal carcinogenesis and subsequent progression, aggressiveness, and induced chemoresistance by ACC1- and ACLY-mediated lipogenesis and lipid droplet assembly.

Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism.

To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance.

We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC. The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells. We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells. Finally, we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells.

Compared to normal mucosa, REG4 mRNA expression was high in CRC (P < 0.05) but protein expression was low. An inverse correlation existed between lymph node and distant metastases, tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression (P < 0.05), but vice versa for REG4 protein expression. REG4-related genes included: Chemokine activity; taste receptors; protein-DNA and DNA packing complexes; nucleosomes and chromatin; generation of second messenger molecules; programmed cell death signals; epigenetic regulation and DNA methylation; transcription repression and activation by DNA binding; insulin signaling pathway; sugar metabolism and transfer; and neurotransmitter receptors (P < 0.05). REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration, and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly. REG4 inhibited the transcription of acetyl-CoA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti-acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.

REG4 may be involved in chemoresistance through lipid droplet assembly. REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.

Little is known about the role of chromosome 12 open reading frame 49 (C12ORF49)-induced metabolic signal transduction in tumor growth. We investigated the relationship between C12ORF49 expression and prognosis in colorectal cancer (CRC) patients.

C12ORF49 protein expression was measured in CRC tissues by Western blot and immunohistochemistry staining. Knock out of C12ORF49 in CRC cells was then performed, and the role of C12ORF49 in CRC cell proliferation and growth was examined. The expression of C12ORF49 in CRC was analyzed in Gene Expression Profiling Interactive Analysis (GEPIA) databases. A prognosis model with 11 C12ORF49-associated genes (CAGs) was generated by TCGA databases.

C12ORF49 expression was significantly higher in CRC tumor tissue than in non-tumor tissue. Furthermore, in vitro and in vivo loss-of-function experiments, showed that C12ORF49 plays critical roles in promoting tumor cell growth. There was a significant correlation between C12ORF49 protein and the presence of tumor necrosis. C12ORF49 is critical for its interaction with SREBF1, TMEM41A, and S1PR3 in the poor prognosis of CRC.

Our results suggest that C12ORF49 plays a key role in CRC tumor growth.

Dermatomyositis (DM) is a rare autoimmune disease characterized by severe muscle dysfunction, and the immune response of the muscles plays an important role in the development of DM. Currently, the diagnosis of DM relies on symptoms, physical examination, and biopsy techniques. Therefore, we used machine learning algorithm to screen key genes, and constructed and verified a diagnostic model composed of 5 key genes. In terms of immunity, The relationship between 5 genes and immune cell infiltration in muscle samples was analyzed. These diagnostic and immune-cell-related genes may contribute to the diagnosis and treatment of DM.

GSE5370 and GSE128470 datasets were utilised from the Gene Expression Omnibus database as DM test sets. And we also used R software to merge two datasets and to analyze the results of differentially expressed genes (DEGs) and functional correlation analysis. Then, we could detect diagnostic genes adopting least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) analyses. The validity of putative biomarkers was assessed using the GSE1551 dataset, and we confirmed the area under the receiver operating characteristic curve (AUC) values. Finally, CIBERSORT was used to evaluate immune cell infiltration in DM muscles and the correlations between disease-related biomarkers and immune cells.

In this study, a total of 414 DEGs were screened. ISG15, TNFRSF1A, GUSBP11, SERPINB1 and PTMA were identified as potential DM diagnostic biomarkers(AUC > 0.85),and the expressions of 5 genes in DM group were higher than that in healthy group (p < 0.05). Immune cell infiltration analyses indicated that identified DM diagnostic biomarkers may be associated with M1 macrophages, activated NK cells, Tfh cells, resting NK cells and Treg cells.

The study identified that ISG15, TNFRSF1A, GUSBP11, SERPINB1 and PTMA as potential diagnostic biomarkers of DM and these genes were closely correlated with immune cell infiltration.This will contribute to future studies in diagnosis and treatment of DM.

The hallmark feature of metabolic reprogramming is now considered to be widespread in many malignancies, including colorectal cancer (CRC). Of the gastrointestinal tumors, CRC is one of the most common with a high metastasis rate and long insidious period. The incidence and mortality of CRC has increased in recent years. Metabolic reprogramming also has a significant role in the development and progression of CRC, especially lipid metabolic reprogramming. Many studies have reported that lipid metabolism reprogramming is similar to the Warburg effect with typical features affecting tumor biology including proliferation, migration, local invasion, apoptosis, and other biological behaviors of cancer cells. Therefore, studying the role of lipid metabolism in the occurrence and development of CRC will increase our understanding of its pathogenesis, invasion, metastasis, and other processes and provide new directions for the treatment of CRC. In this paper, we mainly describe the molecular mechanism of lipid metabolism reprogramming and its important role in the occurrence and development of CRC. In addition, to provide reference for subsequent research and clinical diagnosis and treatment we also review the treatments of CRC that target lipid metabolism.

Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.