Breast cancer is the most common malignant tumor threatening women's health. Alteration in lipid metabolism plays an important role in the occurrence and development of many diseases, including breast cancer. The uptake, synthesis, and catabolism of lipids in breast cancer cells are significantly altered, among which the metabolism of fatty acids, cholesterols, sphingolipids, and glycolipids are most significantly changed. The growth, progression, metastasis, and drug resistance of breast cancer cells are tightly correlated with the increased uptake and biosynthesis of fatty acids and cholesterols and the up-regulation of fatty acid oxidation. Cholesterol and its metabolite 27-hydroxycholesterol promote the progression of breast cancer in a variety of ways. The alteration of lipid metabolism could promote the epithelial-mesenchymal transition of breast cancer cells and lead to changes in the tumor immune microenvironment that are conducive to the survival of cancer cells. While the accumulation of ceramide in cancer cells shows an inhibitory effect on breast cancer. This review focuses on lipid metabolism and elaborates on the research progress of the correlation between different lipid metabolism and the growth, progression, and drug resistance of breast cancer.

Cathepsins, a group of lysosomal peptidases, have traditionally been recognized as tumor facilitators. Recent research, however, highlights their critical role in orchestrating cancer and the tumor microenvironment (TME). Primality, cathepsins degrade extracellular matrix, enabling cancer cells to invade and metastasize, while also promoting vascular endothelial infiltration and subsequent angiogenesis. Additionally, cathepsins boost fibroblast growth, thereby supporting tumor progression. More importantly, cathepsins are pivotal in modulating immune cells within the TME by regulating their recruitment, antigen processing and presentation, differentiation, and cell death, primarily contributing to immune suppression. Given their overexpression in tumors and elevated levels in the circulation of cancer patients, it is crucial to consider the systemic effects of cathepsins. Although the comprehensive role of cathepsins in cancer patients' bodies remains underexplored, they likely influence systemic immunity and inflammation, cellular metabolism, muscle wasting, and distant metastasis through their unique proteolytic functions. Notably, cathepsins also confer resistance to chemoradiotherapy by rewriting the cellular profile within the TME. In this context, promising results are emerging from studies combining cathepsin inhibitors with conventional therapies to suppress tumor development effectively. This review aims to decipher the cathepsin-driven networks within cancer cells and the TME, detailing their contribution to chemoradioresistance by reshaping both micro- and macroenvironments. Furthermore, we explore current and future perspectives on therapies targeting cathepsins' interactions, offering insights into innovative treatment strategies.

Breast cancer (BC) is one of the most common human malignancies, but the mechanisms of BC have not been fully elucidated. Recently, tetraspanin 31 (TSPAN31) is reported to be linked to cancer progression. However, the function of TSPAN31 remains unclear in BC. Investigation of the function and potential mechanism of TSPAN31 in BC was the purpose of this study. Immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction were applied to measure TSPAN31 expression. Loss and gain functional experiments were utilized to survey the influences of TSPAN31 on BC biological process, including cell growth, invasion, migration, and fatty acid metabolism. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis based on DepMap database and Gene Set Enrichment Analysis based on The Cancer Genome Atlas database were executed to find TSPAN31-related pathway. Western blot was carried out to assess the changes of fatty acid synthase (FASN), sterol regulatory element binding protein 1 (SREBP1), acyl-CoA synthetase long-chain family member 1 (ACSL1), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-PI3K, protein kinase B (AKT), and p-AKT. In human non-triple negative breast cancer tissues and cells, TSPAN31 expression was upregulated. TSPAN31 knockdown induced BC cell apoptosis, inhibited cell proliferation, invasion, migration, and fatty acid metabolism, and reduced the protein levels of FASN, SREBP1, ACSL1, p-PI3K/PI3K, and p-AKT/AKT. In contrast, TSPAN31 overexpression led to the opposite results. Additionally, the activator of PI3K (740 Y-P) attenuated the inhibition of TSPAN31 knockdown on fatty acid metabolism, proliferation, and invasion in BC cells. Through activation of fatty acid metabolism and PI3K/AKT pathway, TSPAN31 played a carcinogenic role in BC. For the mechanism of BC tumorigenesis, our study provides an interesting insight.

The methoxylated modification of flavonoids has been reported to enhance stability and permeability; however, its effect on the improvement of activity is not clear. In this study, Citrus depressa flavonoid O-methyltransferase 5 and Sorghum vulgare 7-O-methyltransferase were recombinantly expressed and successfully converted quercetin (QUE) into eight methoxylated products, which were isolated and identified with a purity exceeding 95%. All products except rhamnetin (RHA) showed improved stability, while only 5,7,3',4'-EMQ, 7,3',4'-TMQ, and 3,7,3',4'-EMQ had higher uptake ratios. Compared to QUE, 5,7,3',4'-EMQ and RHA significantly reduced the intracellular triglyceride level, while 3,5,7,3',4'-PMQ, 3,3',4'-TMQ and 3,7,3',4'-EMQ increased it. 5,7,3',4'-EMQ and RHA also significantly downregulated both the mRNA and protein levels of peroxisome proliferator-activated receptor γ, while 3,5,7,3',4'-PMQ and 3,7,3',4'-EMQ upregulated PPARγ at the transcriptional level to about ten times higher than that of QUE. The structure-activity relationship analysis highlighted the importance of C3-OH retention and dual methoxylation of the A-ring. In summary, this study efficiently produced eight structurally well-defined QUE methoxylation products via biotransformation, established an in vitro initial structure-activity relationship for regulating adipogenesis, and provided a potential structure for PPARγ regulation, a central target of lipid metabolism.

Hepatocellular Carcinoma (HCC) is related to dysregulated lipid metabolism and immunosuppressive microenvironment. This study developed a genetic risk model using lipid metabolism-related genes to predict survival and immune patterns in HCC patients.

Differentially expressed genes (DEGs) related to lipid metabolism were identified in HCC via the TCGA-LIHC dataset. A risk model for survival prediction was constructed via DEGs related to survival. The immune signature associated with the risk model was also evaluated by the CIBERSORT algorithm, tumor immune dysfunction and exclusion algorithm, and single sample gene set enrichment analysis.

This study identified six lipid metabolism-related genes, ADH4, LCAT, CYP2C9, CYP17A1, LPCAT1, and ACACA, to construct a lipid metabolism-related gene risk model that can divide HCC patients into low- and high-risk groups. Internal and external validation verified that the risk model could be a signature that could effectively predict HCC patient prognosis. High-risk patients showed disrupted immune cell profiles, reduced tumor-killing capacity, and increased expression of immune checkpoint genes. However, they responded more favorably to immune checkpoint inhibitor (ICB) therapy. The top ten hub genes related to the risk model were associated with tumor progression and deteriorating prognosis. In vitro experiments verified that the downregulation of the top 1 hub gene CDK1 was correlated to the HCC cell proliferation.

The risk model constructed using lipid metabolism-related genes could effectively predict prognosis and was related to the immunosuppressive microenvironment and ICB immunotherapy. The hub genes related to the risk model were potential therapeutic targets.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is often diagnosed at a late stage, resulting in poor survival rates and limited treatment options. Several factors contribute to the dismal prognosis of PDAC, including the absence of reliable biomarkers and effective therapies, as well as the complex biology of the disease.

The pathobiology of PDAC encompasses its unique mutational landscape, desmoplastic stroma, and immune suppressive tumor microenvironment (TME). These characteristics are influenced by an intricate network of signaling pathways activated by oncogenic KRAS, DNA damage and repair machinery, metabolic adaptations, and aberrant mucin expression. This review summarizes our current understanding of these pathways to explore their potential for therapeutic vulnerabilities in PDAC. We discuss how recent efforts to elucidate these pathways have identified novel targets and treatments for this dreadful disease.

The complex biology of PDAC complicates the effectiveness of single therapeutic agents. To achieve durable clinical responses in patients with PDAC, it is essential to simultaneously inhibit multiple parallel or unrelated pathways. Therefore, a combination therapeutic regimen is necessary to significantly improve treatment outcomes that rely solely on biologically driven concepts. These studies suggest ways to expand our understanding of the therapeutic vulnerabilities in PDAC.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors of the digestive system, and its prevalence is currently increasing. The current study aims to elucidate the mechanism by which membrane-associated RING-CH8 (MARCH8) impedes the progression of HCC. MARCH8 was identified as a distinct prognostic marker for recurrence-free survival (RFS) and overall survival (OS) in patients with HCC. This study shows that MARCH8 hinders lipid deposition by suppressing the expression of key enzymes for the de novo synthesis of fatty acids (FAs) via RNA sequencing, untargeted metabolomics, and a series of in vivo and in vitro experiments. Further experimental validation demonstrated that MARCH8 was a novel E3 ligase of sterol regulatory element binding protein 1 (SREBP1). And, it primarily promoted the degradation of SREBP1, thereby suppressing the expression of key enzymes involved in the de novo synthesis of FAs. In conclusion, this study has identified MARCH8 as a key "switch" that can be targeted to prevent de novo FA synthesis in HCC cells. This finding may have substantial implications for discovering innovative therapeutic strategies for HCC.

Lipid droplets (LDs) are essential organelles used to store lipids and participate in cellular lipid metabolism. Imaging LDs is an intuitive approach to comprehend their biological functions. Herein, the LDs-targeted CDs (LD-CDs) featuring robust solvatochromic emission were elaborately designed by a Schiff base reaction using 1, 2-diamino-4-fluorobenzene, 3-dimethylaminophenol, and thiourea as precursors. The LD-CDs exhibited a remarkable sensitivity to polarity changes over a broad linear range (0.0205-0.3213), owing to its unique intramolecular charge transfer effect (ICT). Moreover, the favorable lipophilicity of LD-CDs endows it with the capability to light up LDs with high specificity. Due to their good lipophilicity and biocompatibility, the LD-CDs were able to differentiate cancer cells from normal cells and keep real-time track of LDs dynamic behaviors, including dissociation, migration, and fusion. Leveraging the multifunctionality of LD-CDs, we have also observed the dynamic changes of lysosomes and LDs during lipophagy. Additionally, the LD-CDs were employed to reveal the polarity change of LDs in living cells and zebrafish under oleic acid stimulation and to visualize lipid metabolism in zebrafish. We deem that this work will expand the applications of CDs in biological imaging and make further contributions to the field of LDs-associated metabolism and diseases.

Low-density lipoprotein receptor-related protein 8 (LRP8) is a crucial regulator of lipid metabolism and is implicated in the development and treatment of various cancers. However, its role in bladder cancer (BCa) remains unknown. We analyzed LRP8 expression in BCa using the TCGA database and clinical samples. We manipulated LRP8 expression in tumor cell lines using siRNA or overexpression plasmid transfection. Cell proliferation, migration, invasion, apoptosis, and drug resistance were assessed through CCK-8, transwell, flow cytometry, and IC50 assays. Additionally, a rescue experiment confirmed the association between LRP8 and lipid metabolism. LRP8 was significantly upregulated in BCa tissues and cells. Knockdown of LRP8 reduced tumor cell proliferation, migration, invasion, and increased apoptosis while enhancing cisplatin sensitivity. Overexpression of LRP8 boosted malignant progression and cisplatin resistance in tumor cells. The expression level of LRP8 is positively linked with the expression of lipid metabolism-related genes, phospholipid accumulation, and triglyceride accumulation. Notably, inhibiting lipid metabolism reversed the malignant progression and cisplatin resistance induced by LRP8 overexpression. LRP8 could promote BCa malignant progression and cisplatin resistance through lipid metabolism regulation.

Most forms of obesity are associated with chronic diseases that remain a global public health challenge.

Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation.

This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood.

The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies.

The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity.

This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.

Liver plays a pivotal role in maintaining energy homeostasis during fasting-refeeding transition. We previously reported that fasting-refeeding induces the dynamic changes of liver size. However, the alterations in hepatic lipid profiles during these dynamic changes remain unclear. Therefore, the present study aimed to clarify the effect of fasting and refeeding on hepatic lipid homeostasis in mice using lipidomics analysis and to identify the specific lipids that vary during the fasting-refeeding transition. In this study, C57BL/6 mice were fasted for 24 h and subsequently refed for 1, 3, 6, 12, and 24 h, respectively. Liver and serum samples were collected at each time point for further analysis. The results demonstrated that fasting obviously decreased the liver size accompanying with hepatic lipid accumulation, which were all returned to normal level after refeeding. Lipidomics analysis revealed that a total of 309 lipids were significantly disturbed, over half of them belonged to triacylglycerol (TG). Consistently, fasting significantly altered the expression of genes associated with fatty acid uptake, TG synthesis and metabolism, which were returned to baseline level after refeeding. In conclusion, these findings demonstrated that fasting induced liver shrinkage and the change of lipid profiling, especially TG accumulation in liver, while these effects can be reversed after refeeding.

While metabolic pathway alterations are linked to colorectal cancer (CRC), the predictive value of pre-diagnostic metabolomic profiling in CRC risk assessment remains to be clarified. This study evaluated the predictive performance of a metabolomics risk panel (MRP) both independently and in combination with established risk factors.

We derived, internally validated (IV), and externally validated (EV) a metabolomics risk panel (MRP) for CRC from data of the UK Biobank (UKB) and the German ESTHER cohort. Baseline blood samples were assessed for 249 metabolites using nuclear magnetic resonance spectroscopy analysis. We applied LASSO Cox proportional hazards regression to identify metabolites for inclusion in the MRP and evaluated the model performance using the concordance index (C-index). We compared the performance of the MRP to an environmental risk panel (ERP; sex, age, body mass index, smoking status, and alcohol consumption) and a genetic risk panel (GRP; polygenic risk score).

The study included 154,892 participants of the UKB cohort (mean age at baseline 54.5 years; 55.5% female) with 1879 incident CRC and 3242 participants of the ESTHER cohort (mean age 61.5 years; 52.2% female) with 103 CRC cases. Twenty-three metabolites, primarily amino acid and lipid-related metabolites, were selected for the MRP, showing moderate predictive performance (C-index 0.60 [IV] and 0.54 [EV]). The ERP and GRP showed superior performance, with C-index values of 0.73 (IV) and 0.69 (EV). Adding the MRP to these risk models did not change the C-indices in both cohorts.

Genetic and environmental risk information provided strong predictive accuracy for CRC risk, with no improvements from adding metabolomics data. These findings suggest that metabolomics data may have limited impact on enhancing established CRC risk models in clinical practice.

Obstructive sleep apnea (OSA) increases the risk of all-cause and cardiovascular mortality. This study aimed to investigate the association between OSA and atherogenic risk in the Koreans.

Data from 8,158 participants (mean age, 57.9 ± 11.7; male/female, 1:1.4) obtained from the Korea National Health and Nutrition Examination Survey between 2019 and 2021. OSA risk was screened using the STOP-BANG score, and atherogenic risk was measured using the atherogenic index of plasma (AIP). Logistic regression was used to evaluate the association between the STOP-BANG scores and high AIP and subgroups according to the presence of diabetes.

The proportions of individuals with atherogenic risk (AIP > 0.24) were 13.7%, 27.6%, and 34.7% in the low-, intermediate-, and high-OSA risk groups (p < 0.001). After adjustment, individuals with intermediate and high OSA risk had 1.35 (95% confidence interval [CI], 1.16-1.58; p < 0.001) and 1.32 (95% CI, 1.08-1.61; p = 0.006) times higher odds of having atherogenic risk than those with low OSA risk. Among patients without diabetes, high OSA risk was not an independent factor affecting atherogenic risk (hazard ratio [HR], 1.17; 95% CI, 0.93-1.47). However, among patients with diabetes, compared with those with low OSA risk, those with intermediate (HR, 1.51; 95% CI, 1.05-2.19) and high OSA risk (HR, 1.58; 95% CI, 1.02-2.46) had significantly increased atherogenic risk.

OSA is linked to increased atherogenic risk in the Koreans, especially in individuals with diabetes, thus highlighting the importance of routine OSA screening to manage and reduce cardiovascular risks.

Transarterial radioembolization (TARE) is a primary palliative treatment for advanced liver cancer. Nonetheless, its therapeutic efficacy is frequently hindered by resistance to tumor cell apoptosis induced by inter-radiotherapy. Induction of multiple cell death modalities provides a potential solution to this challenge. Ferroptosis, a distinct form of cell death from apoptosis, is dependent on the intracellular Fe2+-mediated Fenton reaction for the production of hydroxyl radicals (·OH) and is gaining recognition as a promising approach for cancer treatment. In this study, we synthesized a therapeutic radionuclide iodine-131 (131I)-based TARE agent by combining 131I-labeled iron-based MIL-88B(Fe) nanoparticles (NPs) (abbreviated as 131I-MIL-88B(Fe)) with Lipiodol to achieve a combined apoptosis-ferroptosis tumor therapy. Specifically, a mixture of Lipiodol and 131I-MIL-88B(Fe) NPs was injected into the liver tumors through the hepatic artery. Lipiodol blocks the arterial blood supply of the tumor, causing tumor tissue necrosis, whereas 131I inter-radiotherapy damages deoxyribonucleic acid (DNA) through direct action or indirectly via the production of ·OH through H2O radiolysis, leading to tumor cell apoptosis. Importantly, hydrated electrons (eaq-), a byproduct of H2O radiolysis, promoted the conversion of Fe3+ to Fe2+ in MIL-88B(Fe) NPs, enhancing the efficacy of the Fenton reaction and triggering ferroptosis. In vitro experiments demonstrated that compared to 131I alone, 131I-MIL-88B(Fe) NPs significantly enhanced ferroptosis-mediated tumor cell death due to 131I-induced Fe2+ production, which increased catalytic activity in the Fenton reaction. In a rat model bearing orthotopic N1S1 liver tumors, TARE with Lipiodol and 131I-MIL-88B(Fe) NPs induced tumor cell necrosis, apoptosis, and ferroptosis, resulting in improved therapeutic outcomes. This study leverages eaq- to facilitate Fe3+/Fe2+ conversion for efficient ferroptosis, turning waste into a valuable resource. This demonstrated the innovative integration of multiple treatment strategies to augment the efficacy of TARE in liver cancer therapy.

Hepatocellular carcinoma (HCC) is among the most aggressive malignancies, marked by high recurrence rates and limited treatment efficacy, especially in HBV-associated HCC (HBV-HCC). This subtype exhibits pronounced metabolic reprogramming, with lipid synthesis playing a pivotal role in driving tumor aggressiveness and therapeutic resistance. However, the molecular mechanisms underlying this metabolic shift remain unclear. In our study, analysis of the LIHC-TCGA database and comparisons between HCC tissues and adjacent peri-tumoral tissues revealed that 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is significantly upregulated in HBV-HCC. Moreover, elevated PFKFB4 expression correlates with poorer prognosis and unfavorable overall survival among HBV-HCC patients. Functional assays demonstrated that PFKFB4 promotes HCC proliferation by enhancing glycolysis and de novo lipid synthesis. Notably, PFKFB4 not only increases glycolytic flux but also upregulates sterol regulatory element-binding protein 1 (SREBP1) expression via its enzymatic activity. Mechanistically, PFKFB4 suppresses phosphorylated AMP-activated protein kinase (p-AMPK) through enhanced aerobic glycolysis, which in turn stimulates the level of SREBP1. Collectively, these findings position PFKFB4 as a critical mediator of metabolic reprogramming in HBV-HCC and a promising therapeutic target.

Immunotherapy has transformed the landscape of melanoma treatment, offering significant extensions in survival for many patients. Despite these advancements, nearly 50% of melanoma cases remain resistant to such therapies, highlighting the need for novel approaches. Emerging research has identified lipid metabolism reprogramming as a key factor in promoting melanoma progression and resistance to immunotherapy. This reprogramming not only supports tumor growth and metastasis but also creates an immunosuppressive environment that impairs the effectiveness of treatments such as immune checkpoint inhibitors (ICIs). This review delves into the intricate relationship between lipid metabolism and immune system interactions in melanoma. We will explore how alterations in lipid metabolic pathways contribute to immune evasion and therapy resistance, emphasizing recent discoveries in this area. Additionally, we also highlights novel therapeutic strategies targeting lipid metabolism to enhance immune checkpoint inhibitor (ICI) efficacy.

Abnormal metabolism is a characteristic of malignant tumors. Numerous factors play roles in the regulation of tumor metabolism. As epigenetic regulators, enhancers, especially the super-enhancers (SEs), serve as platforms for transcription factors that regulate the expression of metabolism-related enzymes or transporters at the gene level. In this study, we review the effects of enhancer/ SE-driven genes on tumor metabolism and immunity. Enhancers/SEs play regulatory roles in glucose metabolism (glycolysis, gluconeogenesis, tricarboxylic acid (TCA) cycle, pyruvate, and pentose phosphate pathway, lipid metabolism (cholesterol, fatty acid, phosphatide, and sphingolipid), and amino acid metabolism (glutamine, tryptophan, arginine, and cystine). By regulating tumor metabolism, enhancers and SEs can reprogram tumor microenvironment, especially the status of various immune cells. Therefore, interfering enhancers/SEs that regulate the tumor metabolism is likely to enhance the effectiveness of immunotherapy.

Bladder cancer (BLCA) is one of the most common tumors of the urinary tract. The diagnosis of BLCA is mostly by invasive tests, which are damaging and unsuitable for early screening. Current non-invasive diagnostic modalities are insufficient in sensitivity and specificity. Therefore, novel diagnostic markers are urgently needed to facilitate early detection of bladder cancer. tRNA-derived small RNAs (tsRNAs) are considered to be novel and potentially biologically functional non-coding RNAs (ncRNAs). tsRNAs have been used to help early diagnosis of a variety of tumors. However, whether tsRNAs in BLCA are altered or involved in BLCA progression or regulation remains unclear. Here, we identified a group of up-regulated tsRNAs in BLCA by sequencing tsRNAs in the plasma of BLCA patients and normal controls and further screened two highly correlated tsRNAs with BLCA in the training set and validation set, which were named as tRF-1:28-chrM.Ser-TGA and tiRNA-1:34-Glu-CTC-1-M2. ROC analyses of the expression profiles of these two tsRNAs by the validation set identified a high diagnostic value. We also found that circulating tRF-1:28-chrM.Ser-TGA and tiRNA-1:34-Glu-CTC-1-M2 were specifically expressed and released by BLCA cells and were positively correlated with the degree of disease malignancy. In vitro and in vivo experiments revealed that the two tsRNAs exacerbated BLCA progression and played a role in promoting tumor lipid metabolism. Our study screened two plasma tsRNAs that could serve as valuable early screening and diagnostic biomarkers for BLCA and is also expected to provide potential novel molecular targets for the treatment of BLCA.

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.

Altered lipid metabolism is a well-known hallmark of cancer. However, the underlying mechanisms of altered lipid metabolism in colorectal cancer (CRC) progression requires further investigation. Previously we have revealed that DEAD-box RNA helicase 21 (DDX21) promotes CRC metastasis via liquid-liquid phase separation. In this study, we identify DDX21 as a novel regulator of lipid metabolism in CRC.

In vitro and in vivo assays illustrated the biological role of DDX21 and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) in CRC lipid metabolism and progression. Bioinformatics analysis, ChIP, meRIP, RIP, RNA stability assay and dual-luciferase reporter assay were applied to explore the underlying molecular mechanisms. The expression levels and prognostic role of YTHDF1/DDX21/HMGCS1 axis in CRC patients were analyzed by immunohistochemical staining and Kaplan-Meier plotter.

DDX21 enhanced CRC progression via promoting lipid metabolism. Mechanistically, YTHDF1 enhanced DDX21 mRNA stability by recognizing its m6A-modified sites. DDX21 further binded to 3‑hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) promoter region and directly activated HMGCS1 transcription. Moreover, our clinical data showed that a simultaneously high expression of YTHDF1, DDX21 and HMGCS1 predicted an unfavorable overall survival in CRC patients.

Our study demonstrates that the YTHDF1/DDX21/HMGCS1 axis promotes CRC progression via regulating lipid metabolism and DDX21 might be a promising target for CRC therapy.

This study aimed to explore the molecular mechanism underlying the prognostic role of ancient ubiquitous protein 1 (AUP1) in head and neck squamous cell carcinoma (HNSCC) and its relationship with the tumor immune microenvironment. Various web resources were used to analyze the differential expression of AUP1 and its role in the HNSCC pathogenesis. A nomogram aimed at predicting 1-, 3-, and 5-year survival rates was developed based on the patient's clinicopathological characteristics and AUP1 expression pattern. Several algorithms and analytical tools were used to explore the correlation between AUP1 expression and sensitivity to immune checkpoint gene therapy by evaluating infiltrating immune cells in patients with HNSCC. Higher AUP1 mRNA and protein expression levels were observed in most tumors and HNSCC than in the normal tissues. High AUP1 expression was an independent predictive risk factor for the overall survival of patients as it was closely associated with the patients' T, M, clinical, and pathological stages and lymphovascular invasion in HNSCC. In conclusion, AUP1 is involved in the occurrence and progression of HNSCC, may be used as an independent prognostic factor in patients with HNSCC, and could serve as a potential intervention target to improve immunotherapy sensitivity in HNSCC.

The chemokine CXCL6 is identified as a pivotal regulator of biological processes across multiple malignancies. However, its function in cholangiocarcinoma (CCA) is underexplored. Tumor profiling for CXCL6 is performed using a public database. Both in vitro and in vivo experiments are utilized to evaluate the oncogenic effects of CXCL6 on CCA. Additionally, RNA-Seq is employed to detect transcriptomic changes related to CXCL6 expression in CCA cells and neutrophils. Molecular docking, fluorescence colocalization, and Co-IP are used to elucidate a direct interaction between JAKs and CXCR1/2. Additionally, LC-MS lipidomics and explored the impact of CXCL6 on immunotherapy in vivo. CXCL6 is upregulated in CCA tissues and promoted the proliferation and metastasis of CCA. Mechanistically, CXCL6 regulated the CXCR1/2-JAK-STAT/PI3K axis in CCA via autocrine signaling, leading to lipid metabolic reprogramming, and promoted neutrophil extracellular traps (NETs) formation by activating the RAS/MAPK pathway in neutrophils. Eventually, NETs formation induced immunotherapy resistance in CCA by blocking CD8+T cell infiltration. CXCL6 modulates CCA progression through the CXCR1/2-JAK-STAT/PI3K axis and reshaping its lipid metabolism. CXCL6 also mediates immunotherapy resistance through NETs, which may be a potential therapeutic target and biomarker for CCA.

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.

Tumours reprogram pathways that regulate nutrient uptake and metabolism to meet the biosynthetic, bioenergetic, and redox requirements of cancer cells. This phenomenon is known as metabolic reprogramming and is edited by the deletion of oncogenes and the activation of proto-oncogenes. This article highlights the pathological mechanisms associated with metabolic reprogramming in laryngeal cancer (LC), including enhanced glycolysis, tricarboxylic acid cycle, nucleotide synthesis, lipid synthesis and metabolism, and amino acid metabolism, with a special emphasis on glutamine, tryptophan, and arginine metabolism. All these changes are regulated by HPV infection, hypoxia, and metabolic mediators in the tumour microenvironment. We analyzed the function of metabolic reprogramming in the development of drug resistance during standard LC treatment, which is challenging. In addition, we revealed recent advances in targeting metabolic strategies, assessing the strengths and weaknesses of clinical trials and treatment programs to attack resistance. This review summarises some currently important biomarkers and lays the foundation for therapeutic pathways in LC.

Agrimonia Pilosa is a traditional Chinese medicine with a long history, which is often used in clinic alone or in combined with other Chinese herb medicine to anti-inflammatory, hemostasis and treat many types cancers, including lung cancer. Agrimonia Pilosa Extract (APE) is extracted from the Agrimonia Pilosa. The potential molecular mechanism of APE on the non-small cell lung cancer remains unclear.

The aim of this study was to investigate the molecular mechanism of APE induced apoptosis in NSCLC cells and its effect on metabolism.

Constructed mouse transplantation tumor models to evaluate the anti-tumor effect of APE by pharmacodynamics test, histological staining and TUNEL staining. Analyzed alterations in metabolites and metabolic pathways in serum and tumor tissues from tumor-bearing mice by liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics. In addition, the key proteins and genes on the signaling pathway were verified by Western blotting (WB) and real-time fluorescence quantitative PCR(RT-qPCR) to reveal the anti-tumor mechanism of APE.

APE inhibited tumor growth by promoting apoptosis and caused metabolic changes. Specifically, they inhibited the PI3K/AKT/Bcl-2 signaling pathway while upregulating apoptotic markers such as TP53, Bax, Caspase-3, and Cytochrome c. Through metabolomics analysis of mouse serum and tumor tissue, 120 different metabolites were identified, including glutamate, PC(24:0/18:0), and LysoPE(18:0/0). Among these, 13 serum metabolites were down-regulated, 16 were up-regulated, 28 tumor metabolites were down-regulated, and 63 were up-regulated. Studies indicate that APE can regulate metabolic disorders associated with non-small cell lung cancer by influencing pathways like glycerophospholipid metabolism, amino acid metabolism, and the TCA cycle, thereby inducing cell apoptosis and leading to significant metabolic changes.

In this study, APE affected the apoptosis of non-small cell lung cancer cells by regulating the PI3K/AKT/Bcl-2 signal transduction pathway and various metabolic pathways thereby inhibited the growth of tumor cells.This deepened the understanding of the metabolic characteristics and apoptosis-related pathways in APE intervened NSCLC, and provided a reference for further research on the mechanism of action of its anticancer drugs.

Hepatocellular carcinoma (HCC) has a relatively poor prognosis and a high degree of malignancy. However, the therapeutic drugs are limited. In recent years, abnormal lipid metabolism and its important role in HCC has been reported, and emerging studies found that some formulae and active components of traditional Chinese medicine (TCM) can regulate abnormal lipid metabolism in HCC, showing their good application prospects. Therefore, this article summarizes the changes and the roles of lipid metabolites in HCC progression, and discusses the role of formulae and active components of TCM for the treatment of HCC based on their regulation on abnormal lipid metabolism. A deeper understanding of their relationship may help the precise use of these formulae and active components in HCC.

Hepatocellular carcinoma (HCC) resists immunotherapy due to its immunosuppressive microenvironment. Sarcoma homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) inhibits T cell receptor signaling, and its pharmacological inhibition is limited by poor selectivity and membrane permeability. Here, we generated CRISPR-edited SHP-1-knockout (KO) CD8+ T cells to enhance adoptive therapy against HCC. Single-cell RNA sequencing of HCC patient T cells revealed elevated SHP-1 in exhausted subsets. SHP-1-KO T cells exhibited increased effector memory T cells (TEM) proportions and enhanced IFN-γ/Granzyme B/perforin secretion, improving cytotoxicity against HCC lines. In humanized PDX models, SHP-1-KO T cells demonstrated superior tumor-killing activity. Transcriptomics identified upregulated lipid metabolism pathways, with HMGCR as a hub gene. Combining SHP-1-KO T cells with simvastatin (HMGCR inhibitor) synergistically amplified anti-HCC efficacy. This study proposes a dual strategy combining SHP-1-targeted cell therapy and metabolic modulation to overcome immunotherapy resistance, offering a translatable approach for HCC treatment.

In recent years, the continuous optimization of anti-tumor therapy has greatly improved the cancer-specific survival rate for patients with breast cancer (BC). The prevention and treatment of breast cancer-related heart diseases have become a new breakthrough in improving the long-term survival for BC patient. The cardiac damages caused by BC treatment are increasingly prominent among BC patients, of which ischemic heart disease (IHD) is the most prominent. Besides, the systemic inflammatory response activated by tumor microenvironment c an induce and exacerbate IHD and increase the risk of myocardial infarction (MI). Conversely, IHD can also exert detrimental effects on tumors. MI not only increases the risk of BC, but also induces specialized immune cell to BC and accelerates the progression of BC. Meanwhile, the treatment of IHD can also promote BC metastasis and transition to more aggressive phenotypes. Although BC and IHD are diseases of two independent systems, their crosstalk increases the difficulty of anti-cancer treatment and IHD management, which reduces the survival for both diseases. Therefore, this review mainly explores the mutual influence and underlying mechanisms between BC and IHD, aiming to provide insights for improving the long-term survival for patients with BC or IHD.

Ovarian cancer (OC) is often detected at an advanced stage and has a high recurrence rate after surgery or chemotherapy. Thus, it is essential to develop new strategies for OC treatment. This study tended to investigate the effects of endothelial cell-specific molecule 1 (ESM1) in OC. The impact of ESM1 on lipid metabolism was investigated through the regulation of ESM1 expression. Differential genes regulated by ESM1 were screened by mRNA sequencing. The role of autophagy in ESM1 regulation on lipid metabolism was explored using autophagy inhibitor chloroquine (CQ). Co-IP, dual-luciferase reporter assay, actinomycin D treatment assay, and others were used to analyze the mechanism of ESM1 regulation on lipid metabolism. The xenograft mouse model was constructed to explore the impact of ESM1 regulation on OC development. The regulatory mechanism of ESM1 in OC patient samples was verified by using microarray analysis and the Log-rank (Mantel-Cox) test. After ESM1 silencing, cholesterol synthesis decreased and lipolysis increased. mRNA sequencing revealed that ESM1 regulation on lipid metabolism was related to Beclin 1 (BECN1). In vitro experiments, ESM1 inhibited lipolysis by suppressing BECN1-mediated autophagy. BECN1 expression was regulated by the transcription factor Kruppel-like factor 10 (KLF10). The competitive binding between BECN1 and HSPA5 promoted the ubiquitination degradation of HMGCR, thereby inhibiting cholesterol production. The intervention experiment with exogenous cholesterol showed a positive correlation between m6A reader IGF2BP3 expression and cholesterol content. Mechanistically, IGF2BP3 regulated the stability of ESM1 mRNA. In vivo experiments, ESM1 modified by m6A methylation promoted cholesterol synthesis and inhibited lipolysis. High expression of ESM1 predicted poor prognosis in OC patients. ESM1 regulated lipid metabolism through IGF2BP3/ESM1/KLF10/BECN1 positive feedback, which was a promising target for OC treatment.

Ovarian cancer (OC) is a significant health challenge, yet the mechanisms driving its progression remain unclear. This study explored the role of hexokinase domain-containing protein 1 (HKDC1) in OC, focusing on tumor growth, lipid metabolism, and immune evasion. Human OC cell lines (SKOV3 and HEY) and the murine OC cell line (ID8) were used to knock down and overexpress HKDC1. An ID8-based epithelial OC mouse model was established to validate the in vitro findings. Our results demonstrated that HKDC1 was upregulated in OC and promoted cell proliferation, migration, and invasion. HKDC1 enhanced lipid accumulation by elevating levels of free fatty acids (FFA), triglycerides, phospholipids, cholesterol, and neutral lipid, while upregulating key enzymes (ACC1, FASN, SCD1, HMGCS1, and HMGCR). It promoted immune escape through PD-L1 upregulation, inhibiting T cell proliferation and reducing IFN-γ, granzyme B, and perforin levels while increasing PD-1 levels. HKDC1 knockdown reversed these effects, which were restored by adding FFA. Mechanistically, HKDC1 interacted with and stabilized glucose-6-phosphatase catalytic subunits (G6PC/G6PC2), supporting its tumor-promoting functions. These findings were confirmed in an OC mouse model, highlighting HKDC1 as a key driver of OC progression through lipid biosynthesis and immune suppression, offering potential therapeutic targets.

Altered lipid metabolism is an emerging hallmark of cancer, which is involved in various aspects of the cancer phenotypes. C12ORF49 has recently been identified as a pivotal regulator of sterol regulatory element binding proteins (SREBPs), a family of transcriptional factors that govern lipid biosynthesis. Nevertheless, the function of C12ORF49 in human cancers has not been studied. Here, we show that C12ORF49 levels are higher in HCC tissue than in nearby non-cancerous liver tissue. Additionally, increased C12ORF49 expression is linked to poorer survival outcomes in HCC patients. Functional experiments uncovered that knockdown of C12ORF49 inhibited HCC cell survival and tumor growth by inducing ferroptosis, whereas the opposites were observed upon C12ORF49 overexpression. Mechanistically, C12ORF49 promotes SREBP1/SCD-regulated production of monounsaturated fatty acids, which inhibits ferroptosis in HCC cells. Furthermore, silencing C12ORF49 combined with Sorafenib treatment showed a synergistic effect in inducing HCC cell death. Together, our findings suggest a critical role of C12ORF49 in the evasion of ferroptosis in HCC cells, highlighting the potential of targeting C12ORF49 as a therapeutic strategy to enhance the efficacy of Sorafenib treatment in HCC.

Recent studies have identified the reprogramming of lipid metabolism as a critical hallmark of malignancy. Enhanced cholesterol uptake and increased cholesterol biosynthesis significantly contribute to the rapid growth of tumors, with cholesterol also playing essential roles in cellular signaling pathways. Targeting cholesterol metabolism has emerged as a promising therapeutic strategy in oncology. The sterol regulatory element-binding protein-2 (SREBP2) serves as a primary transcriptional regulator of genes involved in cholesterol biosynthesis and is crucial for maintaining cholesterol homeostasis. Numerous studies have reported the upregulation of SREBP2 across various cancers, facilitating tumor progression. This review aims to provide a comprehensive overview of the structure, biological functions, and regulatory mechanisms of SREBP2. Furthermore, we summarize that SREBP2 plays a crucial role in various cancers and tumor microenvironment primarily by regulating cholesterol, as well as through several non-cholesterol pathways. We also particularly emphasize therapeutic agents targeting SREBP2 that are currently under investigation. This review seeks to enhance our understanding of SREBP2's involvement in cancer and provide theoretical references for cancer therapies that target SREBP2.

Rheumatoid arthritis (RA) is the most common chronic autoimmune arthropathy. If the disease is aggressive or left untreated, it becomes debilitating, affects a patient's functionality, and reduces the quality of life. Disease-modifying anti-rheumatic drugs (DMARDs), both conventional, targeted, and biological, decrease the disease progression and are key components of effective treatment. Recently, there has been a continuous debate about the possible carcinogenicity of various DMARDs. Lung cancer is a leading cause of cancer death worldwide. The available data show an increased risk of lung cancer in RA patients, but the link between RA and cancer is poorly understood. Carcinogenesis in RA seems to be related to chronic inflammation, familial predisposition, risky behaviors (e.g., smoking), and iatrogenic complications. The main mechanisms of carcinogenic processes in patients with RA are the up-regulation of interleukin-6 (IL-6) cytokine production and wingless/integrated WNT signaling. Up-regulation of WNT5A is an important mechanism that links chronic inflammatory pathways to carcinogenesis observed in RA patients. Concomitant up-regulation of transcription factor STAT3 promotes cell proliferation and inhibits apoptosis. Conversely, suppressed inflammatory processes by DMARDs may decrease the risk of lung cancer. In this article, we discuss the molecular mechanisms of lung cancer in RA and the role of DMARDs in this process. Furthermore, we analyze the molecular effect of drug-induced cancer, which affects transcription factors and thus modulates carcinogenic processes. Finally, we describe risk factors and present preventive and therapeutic approaches.

Cancer immunotherapy has achieved unprecedented success in the field of cancer therapy. However, its potential is constrained by a low therapeutic response rate.

Tertiary lymphoid structure (TLS) plays a crucial role in antitumor immunity and is associated with a good prognosis. Metabolic reprogramming, as a hallmark of the tumor microenvironment, can influence tumor immunity and promote the formation of follicular helper T cells and germinal centers. However, many current studies focus on the correlation between metabolism and TLS formation factors, and there is insufficient direct evidence to suggest that metabolism drives TLS formation. This review provided a comprehensive summary of the relationship between metabolism and TLS formation, highlighting glucose metabolism, lipid metabolism, amino acid metabolism, and vitamin metabolism.

In the future, an in-depth exploration of how metabolism affects cell interactions and the role of microorganisms in TLS will significantly advance our understanding of metabolism-enhanced antitumor immunity.

ABCA1 is involved in the development and progression of a wide range of malignant tumors, so to further clarify the role of ABCA1 expression therein, and to search for new breakthroughs in the treatment of tumors and cancers, we launched a thorough pan-cancer analysis of ABCA1.

Based on the manipulation of TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus), Human Protein Atlas (HPA) datasets and various bioinformatics tools, The oncogenic role of ABCA1 in 33 tumor types was explored from six aspects: gene expression, prognosis, variation, immunohistochemistry, correlation of tumor-associated fibroblastic infiltration, and enriched analysis of related genes. The potential value of ABCA1 was also mined, such as: ABCA1 may be a potential marker of tumor metastasis, play a role in cancer resistance, and its expression may inhibit the spread of tumor cells.

Based on the analysis results, we found that ABCA1 is expressed elevated and mutated in tumor samples of 33 cancer types compared with matched normal tissues, and these mutations may be related to the mechanism of cancer, metastatic ability, and prognosis, etc. Meanwhile, we also investigated the correlation between ABCA1 expression and tumor-associated fibroblast infiltration, and described its association with corresponding miRNAs, which can provide scientific basis for clinical diagnosis.

Our study thoroughly illustrates the impact of ABCA1's systemic presence across various forms of cancer. Given its specificity to tumors, ABCA1 holds promise as a biomarker for cancer diagnosis, monitoring for recurrence, and predicting outcomes. Consequently, our research could significantly bolster the case for utilizing ABCA1 in the therapeutic approach to cancer.

Immunogenic cell death (ICD) is a promising cancer therapy where dying tumor cells release damage-associated molecular patterns (DAMPs) to activate immune responses. Recent research highlights the critical role of metabolic reprogramming in tumor cells, including the Warburg effect, oxidative stress, and lipid metabolism, in modulating ICD and shaping the immune microenvironment. These metabolic changes enhance immune activation, making tumors more susceptible to immune surveillance. This review explores the molecular mechanisms linking ICD and metabolism, including mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and ferroptosis. It also discusses innovative therapeutic strategies, such as personalized combination therapies, metabolic inhibitors, and targeted delivery systems, to improve ICD efficacy. The future of cancer immunotherapy lies in integrating metabolic reprogramming and immune activation to overcome tumor immune evasion, with multi-omics approaches and microbiome modulation offering new avenues for enhanced treatment outcomes.

Triple-negative breast cancer (TNBC) is the most malignant breast cancer, highlighting the need for effective immunotherapeutic targets. The immune checkpoint molecule B7-H3 has recently gained attention as a promising therapeutic target due to its pivotal role in promoting tumorigenesis and cancer progression. However, the therapeutic impact of B7-H3 inhibitors (B7-H3i) remains unclear.

Transcriptomic and metabolomic analyses were conducted to explore the underlying mechanisms of B7-H3 inhibition in TNBC. The therapeutic efficacy of the combined treatment strategy was substantiated through comprehensive phenotypic assays conducted in vitro and validated in vivo using animal models.

B7-H3 blockade induces a "primed for death" stress state in cancer cells, leading to distinct alterations in metabolic pathways. Specifically, B7-H3 knockdown activated the AKT signaling pathway and upregulated sterol regulatory element-binding protein 1 (SREBP1), which in turn elevated FASN expression. The simultaneous inhibition of both B7-H3 and FASN more effectively attenuated the malignant progression of TNBC.

Our findings propose an "immune attack-metabolic compensation" dynamic model and suggest the feasibility of a dual-targeting strategy that concurrently inhibits both B7-H3 and FASN to enhance therapeutic efficacy in TNBC patients.

Gastric cancer (GC) is a deadly disease with poor prognosis and few treatment options. Tropomyosin 4 (TPM4) is an actin-binding protein that stabilizes the cytoskeleton of cells and has an unclear role in GC. This study aimed to elucidate the role and underlying mechanisms of TPM4 in GC pathogenesis. The expression and diagnostic and prognostic value of TPM4 in GC were analyzed using bioinformatics. A nomogram based on TPM4 expression was created and validated with an external cohort. TPM4-knockdown GC cells and xenograft models in nude mice were used to study the function of TPM4 in vitro and in vivo. Proteomic and rescue experiments confirmed the regulatory effect of TPM4 on stearoyl-CoA desaturase 1 (SCD1) in GC. Immunohistochemistry verified the expression and correlation of the TPM4 and SCD1 proteins in GC tissues. Our study identified TPM4 as an oncogene in GC, suggesting its potential diagnostic and prognostic value. The TPM4-based nomogram showed potential prognostic value for clinical use. TPM4 knockdown inhibited GC cell proliferation, induced ferroptosis, and slowed tumor growth in vivo, which is achieved by inhibiting SCD1 expression. Immunohistochemical analysis of GC tissues revealed elevated expression levels of both TPM4 and SCD1 proteins, with a positive correlation observed between their expression. TPM4 is a promising target for new diagnostic, prognostic, and therapeutic strategies for GC. Downregulation of TPM4 inhibits GC cell growth and induces ferroptosis by suppressing SCD1 expression.