Cisplatin is a platinum-based drug that is frequently used to treat multiple tumors. The anti-tumor effect of cisplatin is closely related to the tumor immune microenvironment (TIME), which includes several immune cell types, such as the tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and natural killer (NK) cells. The interaction between these immune cells can promote tumor survival and chemoresistance, and decrease the efficacy of cisplatin monotherapy. Therefore, various combination treatment strategies have been devised to enhance patient responsiveness to cisplatin therapy. Cisplatin can augment anti-tumor immune responses in combination with immune checkpoint blockers (such as PD-1/PD-L1 or CTLA4 inhibitors), lipid metabolism disruptors (like FASN inhibitors and SCD inhibitors) and nanoparticles (NPs), resulting in better outcomes. Exploring the interaction between cisplatin and the TIME will help identify potential therapeutic targets for improving the treatment outcomes in cancer patients.

Despite the promise of ferroptosis in cancer therapy, selectively inducing robust ferroptosis in cancer cells remains a significant challenge. In this study, manipulation of fatty acids β-oxidation (FAO) by combination of mild photodynamic therapy (PDT) and inhibition of triglycerides (TGs) synthesis was found to induce robust and iron-independent ferroptosis in cancer cells with dysregulated lipid metabolism for the first time. To achieve that, TGs synthesis inhibitor of xanthohumol (Xan) and FAO initiator of tetrakis (4-carboxyphenyl) porphyrin (TCPP) were co-delivered by a nanoplexes composed of pH-responsive amphiphilic lipopeptide C18-pHis10 and DSPE-PEG2000. TCPP was found to rapidly increase the intracellular ROS under laser irradiation without inducing antioxidant response and apoptosis, activating the AMPK in cancer cells and accelerating mitochondrial FAO. Xan fueled the mitochondrial FAO with substrates by suppressing the conversion of fatty acids (FAs) to TGs. This also led to augmented intracellular polyunsaturated fatty acids (PUFAs) and PUFAs-phospholipids levels, increasing the intrinsic susceptibility of cancer cells to lipid peroxidization. As a result, the excessive ROS generated from the sustained mitochondrial FAO caused remarkably lipid peroxidation and ultimately ferroptosis. Collectively, our study provides a new approach to selectively induce iron-independent ferroptosis in cancer cells by taking advantage of dysregulated lipid metabolism.

Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.

Breast cancer (BC) is the most common diagnosed cancer in the female population. Different near-infrared (NIR)-based technologies have been generally applied for BC clinical treatment. In this study, a novel network construction algorithm based on molecular vertical relationship (NCVR) was proposed to identify key network signals for clinical personalized treatment. In NCVR, the molecular vertical relationship that can be characterized in simple terms was proposed for network construction, thereby facilitating to better advance clinical decision making. To effectively measure the discriminative ability of molecular vertical relationship between different physiological and pathological stages, the joint probability mass function was constructed using sample frequency which can reduce the influence of sample variability caused by individual differences and the probability of over fitting caused by the high complexity of molecular expression data. NCVR was successfully employed to analyze the similarities and differences of living organisms treated by different treatment patterns (i.e., NIR and apoferritin-conjugated cypate (Cy@AFT) + NIR) on BC. The results of similarity analysis indicated that the reprogramming of cellular lipid and energy metabolism may be responsible for the BC cell death induced by treatments. Experimental results of difference analysis suggested that the disruptions in cholesterol metabolism, ferroptosis and severe lipid metabolism imbalances etc. contribute to the enhanced effectiveness of BC treatment with Cy@AFT + NIR. Then, analysis results of genes related to the selected key metabolites further provided deep insights into pathological alterations associated with BC development and illustrated why the performance of Cy@AFT + NIR therapy is better than that of NIR therapy.

The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.

Epithelial-mesenchymal transition (EMT) is a cellular de-differentiation process that provides cells with the increased plasticity and stem cell-like traits required during embryonic development, tissue remodeling, wound healing and metastasis. Morphologically, EMT confers tumor cells with fibroblast-like properties that lead to the rearrangement of cytoskeleton (loss of stiffness) and decrease of membrane rigidity by incorporating high level of poly-unsaturated fatty acids (PUFA) in their phospholipid membrane. Although large amounts of PUFA in membrane reduces rigidity and offers capabilities for tumor cells with the unbridled ability to stretch, bend and twist in metastasis, these PUFA are highly susceptible to lipid peroxidation, which leads to the breakdown of membrane integrity and, ultimately results in ferroptosis. To escape the ferroptotic risk, EMT also triggers the rewiring of metabolic program, particularly in lipid metabolism, to enforce the epigenetic regulation of EMT and mitigate the potential damages from ferroptosis. Thus, the interplay among EMT, lipid metabolism, and ferroptosis highlights a new layer of intricated regulation in cancer biology and metastasis. Here we summarize the latest findings and discuss these mutual interactions. Finally, we provide perspectives of how these interplays contribute to cellular plasticity and ferroptosis resistance in metastatic tumor cells that can be explored for innovative therapeutic interventions.

While nanomaterial-mediated metabolic reprogramming emerges as a promising anticancer strategy, the precise mechanisms remain elusive due to limited metabolomics investigations. The objective of this study is to design an aluminum (Al) based metal organic frameworks (Al-MOF) and investigate its cytotoxic effects on bladder cancer cells (T24), and elucidate the specific molecular mechanisms. Comprehensive characterization (scanning electron microscopy, particle size and potential analysis, infrared spectroscopy, powder X-ray diffraction, and N2 desorption/desorption experiment) confirmed the successful preparation of Al-MOF. Subsequently, in vitro assays demonstrated the selective cytotoxicity of Al-MOF, showing an inhibitory effect on the proliferation of T24 compared to human immortalized urothelial cells. At the same time, when the concentration of Al-MOF exceeded 100 μg/mL, it exhibited significant migration inhibition on T24. Then, the effect of Al-MOF on T24 metabolites was investigated using ultra-high performance liquid chromatography quadrupole Orbitrap high-resolution mass spectrometry. After 24 h of incubation, we identified 38 key differential metabolites from expression patterns and metabolic pathways, predominantly in fatty acid synthesis. Research has found that Al-MOF reduced fatty acid biosynthesis by inhibiting FASN expression, thereby inhibiting the progression of T24. This work provides evidence of MOF-mediated intervention in cancer cell metabolism, offering valuable insights for the design of novel multifunctional nanotherapies.

PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effectiveness. This review provides an overview of the current understanding of resistance mechanisms to PARP inhibitors and explores strategies to overcome these challenges. We discuss the basis of synthetic lethality induced by PARP inhibitors and detail diverse resistance mechanisms affecting PARP inhibitors, including homologous recombination restoration, reduced PARP trapping, enhanced drug efflux, and replication fork stabilization. The review then considers clinical approaches to combat resistance, focusing on combination therapies with immune checkpoint inhibitors, DNA damage response inhibitors, and epigenetic drugs. We also highlight ongoing clinical trials and potential biomarkers for predicting treatment response and resistance. The review concludes by outlining future research directions, emphasizing the need for longitudinal studies, advanced resistance monitoring technologies, and the development of novel combination strategies. By tackling PARP inhibitor resistance, this review seeks to aid in the development of more effective cancer therapies, with the potential to improve outcomes for patients with homologous recombination-deficient tumors.

Metabolic reprogramming occurs alongside tumor development. As cancers advance from precancerous lesions to locally invasive tumors and then to metastatic tumors, metabolic patterns exhibit distinct changes, including mutations in metabolic enzymes and modifications in the activity of metabolic regulatory proteins. Alterations in metabolic patterns can influence tumor evolution, either establishing or alleviating metabolic burdens and facilitating cancer growth. To fully understand how metabolic reprogramming helps tumors grow and find the metabolic activities that are most useful for treating tumors, we need to have a deeper understanding of how metabolic patterns are controlled as tumors grow. Post-translational modifications (PTMs), a critical mechanism in the regulation of protein function, can influence protein activity, stability, and interactions in several ways. In tumor cells, PTMs-mediated metabolic reprogramming is a crucial mechanism for adapting to the challenging microenvironment and sustaining fast growth. This article will deeply explore the intricate regulatory mechanism of PTMs on metabolic reprogramming and its role in tumor progression, with the expectation of providing new theoretical basis and potential targets for tumor treatment.

This study reviews the mechanisms by which obesity affects the development and progression of breast cancer (BC). The association between obesity and BC is mainly due to three aspects: disruption of glycolipid metabolism, abnormal cell function and imbalance of adipokine levels. The dysregulation of glycolipid metabolism caused by obesity, including the accumulation of cholesterol and fatty acids and the reprogramming of glucose metabolism, promotes the growth and invasion of tumour cells. Obesity triggers multiple cellular abnormalities, particularly in lipid-associated macrophages and cancer-associated adipocytes, which promote tumour progression and immunosuppression by secreting inflammatory factors and various fatty acids into the tumour microenvironment. Obesity leads to an imbalance in the expression of several adipokines. Leptin upregulation is closely associated with BC metastasis and resistance to endocrine therapy, while reduced adiponectin levels attenuate the protective effect. At the same time, chronic inflammation and insulin resistance not only further increase the risk of BC, but also exacerbate tumour resistance. In terms of treatment, weight-loss drugs and metformin can improve the efficacy of obesity-related BC treatment to some extent. Intervention strategies targeting adipose tissue remodelling, lipid metabolism and leptin regulation also show potential clinical value, but more research is needed to clarify their safety and efficacy. This review provides systematic ideas and references for research into the mechanisms and clinical management of obesity-related BC.

The goal of this study was to develop a predictive signature using genes associated with fatty acid metabolism to evaluate the prognosis of individuals with gastric cancer (GC).

A total of 24 prognostic-related genes were identified by intersecting differentially expressed genes with 525 fatty acid metabolism (FAM) -related genes and applying a univariate Cox proportional hazards model. By performing consensus clustering of 24 genes associated with FAM, two distinct clusters of GC patients were identified. Subsequently, a risk model was constructed using 39 differentially expressed mRNAs from the two clusters through a random forest model and univariate Cox regression.

An R package, "GCFAMS", was developed to assess GC patients' prognosis based on FAM gene expression. The low-risk group exhibited a more favorable prognosis compared to the high-risk group across various datasets (P < 0.05). The model demonstrated strong predictive performance, with AUC values of 0.86, 0.623, and 0.508 for 5-year survival prediction in the training and two validation datasets. The high-risk group displayed lower IC50 values for embelin and imatinib, suggesting the potential efficacy of these drugs in this subgroup. Conversely, the low-risk group demonstrated an elevated response to immune checkpoints blockade therapy and a higher immunophenoscore, which was further validated in additional cancer cohorts. Public data from single-cell RNA sequencing confirmed that the characterized genes were predominantly expressed in endothelial cells and fibroblasts. Furthermore, the integration of transcriptomics and metabolomics revealed notable variations in fatty acid levels between the clusters, underscoring the clinical relevance of our fatty acid metabolism signature in shaping the metabolic profiles of GC patients.

This developed FAM signature demonstrated potential as a biomarker for guiding treatment and predicting prognosis in GC.

Metabolic rewiring is a hallmark of malignant transformation in leukemic cells and the potential offered by its therapeutic targeting has garnered significant attention. The development of clinically relevant metabolic targeted therapies in acute myeloid leukemia (AML) has mostly focused on targeting mitochondrial energy production, but progress has been hampered by generalized toxicities. An alternative strategy is to shift the focus from targeting energy production to targeting more specialized metabolic functions, such as energy storage, the regulation of oxidative stress and availability of cofactors needed for the function of specific metabolic reactions. Lipid metabolism plays a role in many of these metabolic functions and its importance in AML maintenance and response to therapy is being increasingly recognized but needs to be adequately interpreted in the context of its interaction with the microenvironment, particularly the adipose niche. In this review, we provide an overview of our current understanding of AML cellular metabolic dependencies on fatty acid and lipid metabolism and discuss their relevance in the context of functional interactions with adipocytes. We highlight unresolved questions about how to best target lipid metabolism and suggest approaches needed to fully understand the interplay between malignant cells and their niche in the context of metabolic dependencies.

This study aimed to delineate the protective role of fish oil against alcoholic liver disease (ALD), identify the principal active component between eicosapentaenoic acid (EPA, C20:5 n-3) and docosahexaenoic acid (DHA, C22:6 n-3), and elucidate the molecular mechanisms. C57BL/6J mice were randomly assigned to receive either an alcohol-fed (AF) or pair-fed control (PF) diet, enriched with fish oil (FO) or corn oil (CO) for four weeks. Additionally, a series of in vitro experiments were performed using AML-12 cells to further investigate potential mechanisms. The results showed that plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly lower in the AF-FO group compared to the AF-CO group, indicating that fish oil alleviated alcohol-induced liver damage. Hepatic antioxidant markers, including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were also higher in the AF-FO group than in the AF-CO group. Transcriptomic analysis revealed FO supplementation significantly affected genes involved in oxidoreductase activity and lipid metabolism pathways, with Retsat being the most up-regulated gene. The in vitro experiments indicated that DHA, but not EPA, markedly increased Retsat expression, cell viability, and the expression of genes related to oxidoreductase activity and lipid metabolism, compared to linoleic acid (LA, C18:2 n-6). Notably, knocking down Retsat abolished the protective effects of DHA. In conclusion, dietary fish oil mitigated chronic alcohol-induced liver injury primarily through DHA by upregulating Retsat and downstream genes associated with oxidoreductase function and lipid metabolism.

Fatty acids (FAs) have emerged as significant contributors to tumorigenesis, yet prospective evidence regarding their specific effects on lung cancer risk remains scarce.

To investigate the association between plasma FAs and lung cancer incidence, as well as a potential modification effect of genetic susceptibility on lung cancer risk.

A cohort study was conducted involving 112 547 cancer-free participants from the UK Biobank, with measurements of plasma FAs, including saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs), at baseline (2006-2010). Cox regression models were employed to assess lung cancer risk according to plasma FA quartiles or 1-SD increments. Furthermore, interaction between plasma FAs and polygenic risk score was evaluated using an additive model.

Over an average 10.9-year follow-up, 1122 lung cancer cases occurred. After multivariable adjustment, MUFAs were positively associated with lung cancer risk (hazard ratio [HR] per 1-SD = 1.32; 95% CI, 1.13-1.54). In contrast, PUFAs, particularly n-3 PUFAs, n-6 PUFAs, docosahexaenoic acid, and linoleic acid, were associated with a lower risk of lung cancer, with HRs ranging from 0.79 (95% CI, 0.72-0.87) to 0.89 (95% CI, 0.83-0.95). SFAs were not significantly associated with lung cancer risk. Moreover, we observed an additive interaction between plasma PUFAs and genetic risk. Individuals with a high genetic risk and the lowest quartile of plasma PUFAs had the highest risk of lung cancer (HR = 2.20, 95% CI, 1.43-3.38).

Our findings suggest that plasma PUFAs may serve as protective factors, while MUFAs represent risk factors for lung cancer, offering novel insights into lung cancer carcinogenesis and prevention.

Alpha-fetoprotein (AFP) is a well-known biomarker for liver cancer, and its clinical utility is widely recognized. Recent studies have revealed that AFP plays a multifaceted role in various malignant tumors, including liver cancer. This suggests that AFP is not merely a biomarker but also contributes significantly to the complex process of tumor formation, emphasizing the importance of targeting AFP in therapeutic approaches. Consequently, innovative research and development are essential to overcome the current limitations of AFP-targeted therapies, enhance treatment efficacy, and minimize side effects. This review explores the role of AFP in cancer development and progression, highlights the biological functions of AFP and related pathways, and discusses the clinical implications of AFP-targeted therapies. Ongoing research on AFP will significantly contribute to our understanding of the biological mechanisms of cancer and aid in developing effective and safe treatments. Ultimately, advancements in AFP-targeted therapeutic approaches are expected to play a crucial role in the future of cancer management.

Neuroendocrine neoplasms (NENs) are a group of highly heterogeneous neoplasms originating from neuroendocrine cells with a gradually increased incidence. Metabolic change is one of the recognized markers of tumor progression, which has been extensively and systematically studied in other malignant tumors. However, metabolic change in NENs has been relatively poorly studied, and systematic reviews are lacking. We reviewed the relationship between metabolic changes and NENs from the aspects of glucose metabolism, lipid metabolism, metabolic syndrome, amino acid metabolism and metabolomics, and discussed the potential therapeutic strategies of metabolic changes for NENs.

A new perspective on cancer metabolism suggests that it varies by context and is diverse. Cancer metabolism reprogramming can create a heterogeneous microenvironment that affects immune cell infiltration and function, complicating the selection of treatment methods. However, the specifics of this relationship remain unclear in breast cancer. This research aims to explore how glycolysis and fatty acid metabolism (GF) influence the immune microenvironment and their predictive capabilities for immunotherapy responses and overall survival.

We at first time identified 602 GF-related genes. Utilizing multiple datasets from various centers and employing 10 different machine learning algorithms, we developed a GF-related signature called GFSscore, driven by artificial intelligence.

The GFSscore served as an independent prognostic indicator and demonstrated greater robustness than other models. Its validity was validated through multiple databases. Our study found that breast cancer patients with a high GFSscore, indicative of a greater tendency towards glycolytic activity, experienced poorer prognosis due to immunosuppression from distinct immune evasion mechanisms. Conversely, those with a low GFSscore, more inclined towards fatty acid metabolism, had better outcomes. Additionally, the GFSscore has the potential to forecast how well a patient might respond to immunotherapy and their susceptibility to chemotherapy medications. Moreover, we found that the overexpressed ACSL5 gene inhibits the proliferation of BRCA through experiments.

The GFSscore may offer patients personalized therapy by identifying new therapeutic targets for tumors. By understanding the relationship between cancer metabolism and the immune microenvironment, we can better tailor treatments to individual patients.

Solasonine (SS) has been shown to inhibit the proliferation of various malignant tumors, though its effects on lipid metabolism in tumor cells are less understood. This study investigated SS's anti-tumor mechanism in oral squamous cell carcinoma (OSCC) using lipidomics, cell, and animal models. SS inhibited the growth of CAL27 and WSU-HN30 cells and reduced tumor volume in mice. Lipidomic analysis revealed an increase in diglyceride (DG) and a decrease in triglyceride (TG) levels, alongside a reduction in diacylglycerol acyltransferase 1 (DGAT1), key to TG synthesis. SS also induced reactive oxygen species (ROS) production and mitochondrial damage. Molecular docking confirmed SS's interaction with DGAT1, suggesting it prevents DG to TG conversion, inhibiting OSCC proliferation.

Globally, common gynecological disorders such as Polycystic Ovary Syndrome (PCOS), endometriosis, uterine fibroids (non-malignant gynecological diseases), as well as cervical cancer, uterine cancer, and ovarian cancer (gynecological cancers), profoundly impact women's physical and mental health. The burden of these diseases exhibits significant geographical disparities across different countries and regions, making a comprehensive and precise assessment of the global burden of gynecological diseases particularly crucial. Such an assessment will facilitate the development of region-specific prevention and treatment strategies, contributing to a more effective response to these health challenges.

Incidence, prevalence, mortality rates, and Disability-Adjusted Life Years (DALYs) data for the aforementioned gynecological conditions were obtained from the 2021 Global Burden of Disease (GBD) study and analyzed by age, location, and year. The burden associated with gynecological diseases was analyzed based on the Socio-demographic Index (SDI) and attributable risk factors. The Estimated Annual Percentage Change (EAPC) and its 95% Confidence Interval (CI) were used to assess temporal trends in burden.

In 2021, uterine fibroids were the leading non-malignant gynecological condition contributing to the highest Age-Standardized Incidence Rate (ASIR) and Age-Standardized Prevalence Rate (ASPR), with rates of 250.93 and 2841.07 per 100,000, respectively. Cervical cancer was the main contributor to the Age-Standardized Mortality Rate (ASMR) and Age-Standardized Disability Rate (ASDR) among the eight selected gynecological diseases, with rates of 6.62 and 226.28 per 100,000, respectively. From 1990 to 2021, the ASIR and ASPR for non-malignant gynecological conditions, such as PCOS and uterine fibroids, increased, while the ASDR for PCOS also rose. Among gynecological cancers, the ASIR for uterine cancer increased, while the ASPR for cervical cancer rose. However, the ASIR for cervical and ovarian cancers decreased, along with reductions in the ASMR and ASDR for these cancers and uterine cancer. There were notable regional disparities based on the SDI. In 2021, lower SDI regions had higher incidence, prevalence, mortality rates, and DALYs for endometriosis and cervical cancer, whereas higher SDI regions saw higher rates for PCOS, uterine fibroids, ovarian cancer, and uterine cancer, with more significant mortality and DALYs for ovarian and uterine cancers. The age distribution of these conditions varied. Non-malignant gynecological conditions, such as PCOS and uterine fibroids, primarily affect women aged 30-34 and 40-69. Endometriosis is most common in women aged 20-34, particularly between 25 and 29. Gynecological cancers, including cervical, uterine, and ovarian cancers, predominantly affect women over 35, especially between 40 and 69, with cervical cancer peaking at ages 50-54. Regarding attributable risk factors globally, 1% of cervical cancer deaths were linked to unsafe sexual behaviors, while a high Body Mass Index(BMI) contributed to 0.09% of ovarian cancer deaths and 0.34% of uterine cancer deaths.

The global burden of these six gynecological conditions poses a significant public health challenge. There is an urgent need for international collaboration to advance the development of age and regionally differentiated management strategies for gynecological diseases, including the development of effective diagnostic screening tools and the implementation of high-quality, targeted prevention and treatment strategies.

Metabolic reprogramming is pivotal in malignant transformation and cancer progression. Tumor metabolism is shaped by a complex interplay of both intrinsic and extrinsic factors that are not yet fully elucidated. It is of great value to unravel the complex metabolic activity of tumors in patients. Metabolic flux analysis (MFA) is a versatile technique for investigating tumor metabolism in vivo, it has increasingly been applied to the assessment of metabolic activity in cancer in the past decade. Stable-isotope tracing have shown that human tumors use diverse nutrients to fuel central metabolic pathways, such as the tricarboxylic acid cycle and macromolecule synthesis. Precisely how tumors use different fuels, and the contribution of alternative metabolic pathways in tumor progression, remain areas of intensive investigation. In this review, we systematically summarize the evidence from in vivo stable- isotope tracing in tumors and describe the catabolic and anabolic processes involved in altered tumor metabolism. We also discuss current challenges and future perspectives for MFA of human cancers, which may provide new approaches in diagnosis and treatment of cancer.

Lipid degradation is generally considered an antagonistic pathway to lipid synthesis, so this pathway is often removed to improve lipid production. In this study, triacylglycerol (TAG) cycling formed by lipid degradation is found to be crucial for long-chain polyunsaturated fatty acid (PUFA) biosynthesis; this result contradicts the notion that lipid degradation is a useless process. Specifically, we demonstrate that TAG cycling promoting PUFA biosynthesis occurred in Yarrowia lipolytica and Mortierella alpina via the desaturase/elongase pathway but not in Schizochytrium sp. with the polyketide synthase (PKS) pathway. Exploiting the TAG cycling mechanism, a strategy of decoupling the TAG biosynthesis and degradation is developed. Using this strategy, the titers of C20:5, C22:5 and prostaglandin F2α (PGF2α) in Y. lipolytica are improved by 116.2%, 99.4% and 41.7%, respectively. Our findings highlight the potential of the TAG cycling for related biochemical synthesis in the construction of excellent oleaginous engineered strains.

Noncoding RNAs (ncRNAs) are a class of RNA molecules with little or no protein-coding potential. Emerging evidence indicates that ncRNAs are frequently dysregulated and play pivotal roles in the pathogenesis of pancreatic cancer. Their aberrant expression can arise from chromosomal abnormalities, dysregulated transcriptional control, and epigenetic modifications. ncRNAs function as protein scaffolds or molecular decoys to modulate interactions between proteins and other biomolecules, thereby regulating gene expression and contributing to pancreatic cancer progression. In this review, we summarize the mechanisms underlying ncRNA dysregulation in pancreatic cancer, emphasize the biological significance of ncRNA-protein interactions, and highlight their clinical relevance. A deeper understanding of ncRNA-protein interactions is essential to elucidate molecular mechanisms and advance translational research in pancreatic cancer.

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.

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.

Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.

Clear cell renal cell carcinoma (ccRCC) accounts for 70% of renal cell carcinoma (RCC) cases. Although surgery remains the mainstay treatment, renal injury and high metastasis rates after nephrectomy dramatically reduce patient quality of life. Drugs that stimulate the immune system by targeting checkpoint pathways improve overall survival in patients with RCC. Here, we investigated the applicability of lysophosphatidylcholine acyltransferase 3 (LPCAT3) as a target for immunotherapy.

In the present study, high LPCAT3 expression in ccRCC was identified using The Cancer Genome Atlas (TCGA) data and validated in two external cohorts from the Gene Expression Omnibus (GEO) database. qRT-PCR was performed to identify the mRNA level of LPCAT3 in tumors and adjacent normal tissues. And immunohistochemistry was used to evaluate the protein level of LPCAT3 between two groups of samples. Furthermore, gene set enrichment analysis was performed to explore the biological processes and pathways related to LPCAT3 expression. Key gene expression and correlation analyses were performed to determine the crosstalk among LPCAT3 expression, ferroptosis, and endoplasmic reticulum stress (ERS). Subsequently, CIBERSORT was used to analyze the immune infiltration status of patients with high and low LPCAT3 expression.

TCGA and GEO data revealed that LPCAT3 expression in ccRCC tumor tissues was higher than that in adjacent normal tissues; moreover, patients with high LPCAT3 expression had better survival outcomes. qRT-PCR and immunohistochemistry verified the high LPCAT3 expression in tumor tissue. Pathways related to ferroptosis and ERS were upregulated in patients with high LPCAT3 expression. Univariate and multivariate regression analyses revealed that low LPCAT3 levels represent an independent risk factor for ccRCC. LPCAT3 expression was positively correlated with M2 macrophage infiltration levels but negatively correlated with the memory B cell, CD8+ T cell, follicular helper T cell, regulatory T cell, activated natural killer cell, and activated memory CD4+ T cell infiltration levels.

LPCAT3was identified as a ccRCC biomarker and may regulate immune infiltration and prognosis in ccRCC by mediating ferroptosis and ERS. Thus, it has potential for exploitation as a prognostic and immune therapeutic target for patients with ccRCC.

Glycoproteins, such as Galectin-3 (Gal-3) and Prostate Specific Membrane Antigen (PSMA), are functional proteins involved in numerous biological activities that include cell apoptosis, angiogenesis, and inflammation. Downregulation of both in the highly metastatic human Prostate Cancer (CaP) cell line PC-3 reduces tumor growth. We used Raman Spectroscopy (RS) to examine the effect of a potent Gal-3 inhibitor (GB1107) in CaP cell lines of varying metastatic potential, namely PC-3, DU-145 and LNCaP. All three cancer lines had distinct Raman signatures. Raman spectra from PC-3, DU-145 and LNCaP cells treated with GB1107, compared to the untreated cells as controls, showed significant differences corresponding to changes in phosphatidylinositol (peak at 596 cm-1), O-P-O stretching DNA (786 cm-1), lipid/phospholipid DNA backbone (1090-1100 cm-1), nucleic acid, lipid, protein (amide III) (1296-1305 cm-1), fatty acid (1440 cm-1), and protein (amid I) (1655 cm-1), suggesting that DNA phosphate backbone may become unstable with cancer progression, facilitating cancer cell metastasis. Our data suggests that Gal-3 inhibitor induces significant alterations in major biochemical constituents, such as lipids, proteins, and nucleic acids, which may lead to structural and molecular changes in the cancerous prostate tissue. To further analyze these spectral differences, Singular Value Decomposition (SVD) and Linear Discriminant Analysis (LDA) were applied for classification, enabling effective differentiation between treated and untreated CaP cell lines. This highlights the therapeutic potential of Gal-3 inhibitor in prevention of CaP progression and metastases.

Cancer cells are considered the most adaptable for their metabolic status, which supports growth, survival, rapid proliferation, invasiveness, and metastasis in a nutrient-deficient microenvironment. Since the discovery of altered glucose metabolism (aerobic glycolysis), which is generally known as a part of metabolic reprogramming and an innate trait of cancer cells, in 1930 via Dr. Otto Warburg, numerous studies have endeavored to recognize various aspects of cancer cell metabolism and find new methods for efficiently eradicating described cells by targeting their energy metabolism. In this way, the outcomes have mainly been promising. Accordingly, outlining the related results will indeed assist us in making a definitive path for developing targeted therapy strategies based on cancer cell-altered metabolism. The present study reviews the key features of cancer cell metabolism and treatment strategies based on them. It emphasizes the importance of targeting cancer cell dysregulated metabolic pathways that influence the cell energy supply and manage cancer cell growth and survival. This trial also introduces a multimodal therapeutic strategy hypothesis, a potential next-generation combination therapy approach, and suggests interdisciplinary research to recognize the complexities of cancer metabolism and exploit them for designing more efficacious cancer therapeutic strategies.

Injured or reactive biliary epithelial cells participate in most chronic liver injuries in a process referred to as ductular reaction, which involves multicellular interactions with marked local infiltration of macrophages and fibrogenic cell activation. The direct roles of biliary epithelial cells in shaping their cellular niche remain unknown.

We aimed at investigating the effects of biliary epithelial cell-derived acute phase response protein orosomucoid 2 (ORM2) in shaping monocyte/macrophage response to liver injury.

Transcriptome data sets from human and mouse livers were used, results were confirmed with multiplex immunofluorescence. A multicellular biliary-niche-on-a-chip derived from primary liver and blood cells (wild-type, Mdr2 -/- mice) was established to model ductular reaction. Human blood cells collected from healthy donors and intrahepatic cholangiocyte organoids derived from normal and cirrhotic liver patients were used.

Our transcriptome data set and multiplex immunofluorescence analyses indicated a previously unrecognised involvement of the acute phase response protein ORM2 in ductular reactions in both human and mouse livers. ORM2 gene expression was increased in biliatresone-challenged, bile acid-challenged and acetaminophen-challenged cholangiocytes. Cholangiocyte-derived ORM2 induced unique transcriptome changes and functional adaptation of liver macrophages. ORM2-activated macrophages exacerbated cholangiocyte cell stress and Orm2 expression, but also tended to promote fibrogenic activation of hepatic stellate cells. Mechanistically, ORM2 effects were mediated by an inositol 1,4,5-trisphosphate receptor type 2-dependent calcium pathway.

This study reveals a paracrine communication circuit during ductular reaction, in which reactive cholangiocyte-derived ORM2 reprogrammes liver macrophages, participating in a pathogenic remodelling of the immune biliary niche.

The comprehension of intricate molecular mechanisms underlying how external stimuli promote malignancy is conducive to cancer early prevention. Esophageal squamous cell carcinoma (ESCC) is considered as an external stimuli (hot foods, tobacco, chemo-compounds) induced cancer, characterized by stepwise progression from hyperplasia, dysplasia, carcinoma in situ and invasive carcinoma. However, the underlying molecular mechanism governing the transition from normal epithelium to neoplastic processes in ESCC under persistent external stimuli has remained elusive. Herein, we show that a positive correlation between p38 and ERK1/2 activation during the progression of ESCC. We identify that phosphorylation of ACSL4 at T679 by p38 enhances its enzymatic activity, resulting in increased production of myristoyl-CoA (C14:0 CoA). This subsequently promotes Src myristoylation and activates downstream ERK signaling. Our results partially elucidate the role of ACSL4 in mediating stress-induced signaling pathways that activate growth cascades and contribute to tumorigenesis.

Plasma fatty acids have been linked to various chronic diseases and mortality, but the extent to which fatty acids are associated with the trajectory of multimorbidity remains unclear. We investigated the association of fatty acid profile with multimorbidity trajectories and event-free survival.

Within the UK Biobank, 138,685 chronic disease-free participants were followed for up to 16 years. Seventeen plasma fatty acids were measured by nuclear magnetic resonance. A comprehensive healthy fatty acid score (HFAS) was constructed using LASSO regression. Incidence of chronic diseases and death were ascertained through linkages to medical and death records. Event-free survival was defined as survival without chronic diseases or death. Data were analyzed using a linear mixed-effects model, Cox regression, and Laplace regression.

High HFAS was associated with lower risk of chronic diseases/death (hazard ratio [HR]: 0.907, 95% confidence interval [CI]: 0.888-0.925) and prolonged event-free survival time by 0.636 (95% CI: 0.500-0.774) years compared with low HFAS. High HFAS was also associated with a slower accumulation trajectory of multimorbidity (β: -0.042, 95% CI: -0.045 to -0.038). There was a significant multiplicative interaction between moderate-to-high HFAS and healthy lifestyle on chronic disease/death (p for interaction = .002) and multimorbidity accumulation trajectories (p for interaction < .001).

A healthier plasma fatty acid metabolic profile is associated with a slower accumulation of multimorbidity and prolonged event-free survival time. A healthy lifestyle may strengthen the protective association of HFAS with the risk of chronic diseases/death and the accumulation trajectory of multimorbidity.

Cancer cells exhibit altered metabolism and energetics, prominently reprogramming lipid metabolism to support tumor growth and progression, making it a promising target for cancer therapy. However, traditional genetic and pharmaceutical approaches for disrupting lipid metabolism face challenges due to the adaptability of tumor metabolism and potential side effects on normal tissues. Here, we present a bacteria-based bioorthogonal platform combining transition metal catalysts and Lactobacillus to disrupt the flexible lipid homeostasis in tumors. This platform activates glutamine transporter inhibitors in situ, targeting lipid synthesis in hypoxic tumor environments, while Lactobacillus inhibits lipid accumulation. By disrupting lipid metabolism and glutamine utilization, the present study proposes a safe and potent strategy for cancer therapy, with potential applications for other metabolic diseases.

During the development and progression of lung cancer, cell metabolism function is altered. Thus, cells rely on aerobic glycolysis and abnormal lipid and amino acid metabolism to obtain energy and nutrients for growth, proliferation and drug resistance. Circular RNAs (circRNAs), a class of non-coding RNAs, serve important biological roles in the growth and development of tumors. Functionally, circRNAs act as molecular sponges that absorb microRNAs (miRNAs) and RNA-binding proteins and as protein scaffolds that regulate gene transcription and translation through the maintenance of mRNA stability. In addition, circRNAs are important regulators of tumor metabolism and promote tumor progression through mediating tumor cell proliferation, metastasis and the induction of chemoresistance. Results of previous studies reveal that circRNAs may serve a key role in regulating tumor metabolic processes in lung cancer, through miRNA sponging and alternative mechanisms. Thus, circRNAs demonstrate potential as therapeutic targets for lung cancer. The present study aimed to review the effects of circRNAs on lung cancer cell metabolism and provide novel insights into the clinical treatment of lung cancer. The present review may also provide a novel theoretical basis for the development of lung cancer drug targets.

Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN inhibition, paralleled the sensitivity of PDAC cells to the apoptotic effects of TVB FASNis in conventional PDAC cell lines that naturally express varying levels of FASN. FASN inhibition dramatically increased the sensitivity of "FASN-high" expressing PDAC cells to the BCL2/BCL-XL/BCL-W inhibitor ABT-263/navitoclax and the BCL2-selective inhibitor ABT-199/venetoclax, both in vitro and in in vivo xenografted tumors. The ability of TVB FASNis to shift the balance of pro- and anti-apoptotic proteins and thereby push PDAC cells closer to the apoptotic threshold was also observed in cell lines developed from patient-derived xenografts (PDXs) representative of the classical (pancreatic) transcriptomic subtype of PDAC. Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients.

Osteosarcoma is a common bone tumor in adolescents, which is characterized by lipid metabolism disorders and plays a key role in tumorigenesis and disease progression. Ferroptosis is an iron-dependent form of programmed cell death associated with lipid peroxidation. This review provides an in-depth analysis of the complex relationship between lipid metabolic reprogramming and associated ferroptosis in OS from the perspective of metabolic enzymes and metabolites. We discussed the molecular basis of lipid uptake, synthesis, storage, lipolysis, and the tumor microenvironment, as well as their significance in OS development. Key enzymes such as adenosine triphosphate-citrate lyase (ACLY), acetyl-CoA synthetase 2 (ACSS2), fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1) are overexpressed in OS and associated with poor prognosis. Based on specific changes in metabolic processes, this review highlights potential therapeutic targets in the lipid metabolism and ferroptosis pathways, and in particular the HMG-CoA reductase inhibitor simvastatin has shown potential in inducing apoptosis and inhibiting OS metastasis. Targeting these pathways provides new strategies for the treatment of OS. However, challenges such as the complexity of drug development and metabolic interactions must be overcome. A comprehensive understanding of the interplay between dysregulation of lipid metabolism and ferroptosis is essential for the development of innovative and effective therapies for OS, with the ultimate goal of improving patient outcomes.

Hyperlipidemia, a metabolic disorder marked by dysregulated lipid metabolism, is a key contributor to the onset and progression of various chronic diseases. Maintaining normal lipid metabolism is critical for health, as disruptions lead to dyslipidemia. The gut and liver play central roles in lipid homeostasis, with their bidirectional communication, known as the gut-liver axis, modulated by bile acids (BAs), gut microbiota, and their metabolites. BAs are essential for regulating their own synthesis, lipid metabolism, and anti-inflammatory responses, primarily through the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Available evidence suggests that high-fat diet-induced the gut microbiota dysbiosis can induce "leaky gut," allowing toxic microbial metabolites to enter the liver via portal circulation, triggering liver inflammation and lipid metabolism disturbances, ultimately leading to hyperlipidemia. Extensive studies have highlighted the roles of probiotics and Traditional Chinese Medicine (TCM) in restoring gut-liver axis balance and modulating lipid metabolism through regulating the levels of lipopolysaccharides, short-chain fatty acids, and BAs. However, the therapeutic potential of probiotics and TCM for hyperlipidemia remains unclear. Here, firstly, we explore the intricate interplay among gut microbiota and metabolites, lipid metabolism, gut-liver axis, and hyperlipidemia. Secondly, we summarize the mechanisms by which probiotics and TCM can alleviate hyperlipidemia by altering the composition of gut microbiota and regulating lipid metabolism via the gut-liver axis. Finally, we emphasize that more clinical trials of probiotics and TCM are necessary to examine their effects on lipid metabolism and hyperlipidemia.

The role of human Papillomavirus (HPV) in metabolic reprogramming is implicated in the development and progression of cervical cancer. During carcinogenesis, cancer cells modify various metabolic pathways to generate energy and sustain their growth and development. Cervical cancer, one of the most prevalent malignancies affecting women globally, involves metabolic alterations such as increased glycolysis, elevated lactate production, and lipid accumulation. The oncoproteins, primarily E6 and E7, which are encoded by high-risk HPVs, facilitate the accumulation of several cancer markers, promoting not only the growth and development of cancer but also metastasis, immune evasion, and therapy resistance. HPV oncoproteins interact with cellular MYC (c-MYC), retinoblastoma protein (pRB), p53, and hypoxia-inducible factor 1α (HIF-1α), leading to the induction of metabolic reprogramming and favour the Warburg effect. Metabolic reprogramming enables HPV to persist for an extended period and accelerates the progression of cervical cancer. This review summarizes the role of HPV oncoproteins in metabolic reprogramming and their contributions to the development and progression of cervical cancer. Additionally, this review provides insights into how metabolic reprogramming opens avenues for novel therapeutic strategies, including the discovery of new and repurposed drugs that could be applied to treat cervical cancer.

Fatty acid metabolism (FAM) plays a critical role in tumor progression and therapeutic resistance by enhancing lipid biosynthesis, storage, and catabolism. Dysregulated FAM is a hallmark of prostate cancer (PCa), enabling cancer cells to adapt to extracellular signals and metabolic changes, with the tumor microenvironment (TME) playing a key role. However, the prognostic significance of FAM in PCa remains unexplored.

We analyzed 309 FAM-related genes to develop a prognostic model using least absolute shrinkage and selection operator (LASSO) regression based on The Cancer Genome Atlas (TCGA) database. This model stratified PCa patients into high- and low-risk groups and was validated using the Gene Expression Omnibus (GEO) database. We constructed a nomogram incorporating risk score, clinical variables (T and N stage, Gleason score, age), and assessed its performance with calibration curves. The associations between risk score, tumor mutation burden (TMB), immune checkpoint inhibitors (ICIs), and TME features were also examined. Finally, a hub gene was identified via protein-protein interaction (PPI) networks and validated.

The risk score was an independent prognostic factor for PCa. High-risk patients showed worse survival outcomes but were more responsive to immunotherapy, chemotherapy, and targeted therapies. A core gene with high expression correlated with poor prognosis, unfavorable clinicopathological features, and immune cell infiltration.

These findings reveal the prognostic importance of FAM in PCa, providing novel insights into prognosis and potential therapeutic targets for PCa management.

The specific function of NR4A1 as a transcriptional regulator in cancer remains unclear. Here we report the biological effect of NR4A1 in suppressing breast cancer (BC) growth. We found that NR4A1 deficiency was correlated with BC progression in the clinic. Genetic deletion of NR4A1 in BC cells significantly promoted cellular proliferation and tumor growth. Moreover, global metabolome screening indicated that the deletion of NR4A1 resulted in tumor lipid remodeling and phospholipid accumulation, which was accompanied by increases in fatty acid and lipid uptake. In addition, NR4A1 knockout induced oxidative stress that aggravated redox balance disruption. Mechanistically, transcriptomic and epigenomic analyses revealed that NR4A1 restrained BC cell proliferation by directly interacting with c-Fos and competitively inhibiting c-Fos binding to the promoter of the target gene PRDX6, which is involved in lipid and redox homeostasis. Notably, we confirmed that the treatment of BC cells with the selective NR4A1 agonist cytosporone B significantly activated the expression of NR4A1, followed by increased interaction between NR4A1 and c-Fos, thereby interfering with c-Fos-mediated transcriptional regulation of BC cell growth. Thus, NR4A1 plays a vital role in reducing the c-Fos-induced activation of downstream signaling cascades in BC, suggesting that agents that activate NR4A1 may be potential therapeutic strategies.