Phospholipids, complex lipids prevalent in the human body, play crucial roles in various pathophysiological processes. Beyond their synthesis and degradation, phospholipids can influence chemoresistance by participating in ferroptosis. Extensive evidence highlights the significant link between tumor drug resistance and phospholipids. Therefore, drugs targeting phospholipid metabolism itself or the synthesis of corresponding composite materials will effectively overcome the difficulties of clinical tumor treatment.

Aberrant lipid metabolism is increasingly recognized as a hallmark of cancer, contributing to tumor growth, metastatic dissemination, and resistance to therapy. Cancer cells reprogram key metabolic pathways-including de novo lipogenesis, lipid uptake, and phospholipid remodeling-to sustain malignant progression and adapt to microenvironmental demands. This review summarizes current insights into the role of lipid metabolic reprogramming in oncogenesis and highlights recent advances in lipidomics that have revealed cancer type- and stage-specific lipid signatures with diagnostic and prognostic relevance. We emphasize the dual potential of lipid metabolic pathways-particularly those involving phospholipids-as sources of clinically relevant biomarkers and therapeutic targets. Enzymes and transporters involved in these pathways have emerged as promising candidates for both diagnostic applications and pharmacological intervention. We also examine persistent challenges hindering the clinical translation of lipid-based approaches, including analytical variability, insufficient biological validation, and the lack of standardized integration into clinical workflows. Furthermore, the review explores strategies to overcome these barriers, highlighting the importance of incorporating lipidomics into multi-omics frameworks, supported by advanced computational tools and AI-driven analytics, to decipher the complexity of tumor-associated metabolic networks. We discuss how such integrative approaches can facilitate the identification of actionable metabolic targets, improve the specificity and robustness of lipid-based biomarkers, and enhance patient stratification in the context of precision oncology.

Dyslipidemia is a major contributor to various diseases, including atherosclerotic cardiovascular disease and obesity. Treatment strategies for dyslipidemia continue to evolve as our understanding of this metabolic disorder and potential therapeutic candidates advance. Notably, fucoidan demonstrates promising effects in ameliorating dyslipidemia in rodents, although their lipid metabolism differs significantly from humans. This study, investigates the lipid-regulatory effects of Fucus vesiculosus-derived fucoidan (FvF) and elucidates the underlying mechanisms of action using New Zealand rabbits fed a high-fat diet, whose lipid profiles closely resemble those of patients with dyslipidemia. The results demonstrate that FvF intervention ameliorates dyslipidemia and lipid deposition in a dose-dependent manner. Mechanistically, FvF intervention modulates the expression levels of multiple molecules involved in lipid transport, fatty acid synthesis and beta-oxidation, and redox balance, as revealed by quantitative reverse transcription polymerase chain reaction, western blotting, and proteomic analysis. This study is the first to report that FvF, consisting of alternating [→4)-α-L-Fucp(1 → 3)-α-L-Fucp(1→] glycosyls ameliorates dyslipidemia by directly modulating lipid metabolism and indirectly attenuating oxidative stress. These findings suggest that FvF holds significant potential as a candidate for the treatment of lipid disorder-related diseases.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality due to resistance, metastasis, and recurrence. Unlike conventional cytotoxic therapies, Xingxiao Pills (XXP), a classic traditional Chinese medicine formula, offers a complementary approach to treating LUAD, while its non-cytotoxic anti-cancer mechanisms remain unclear.

To investigate the effect and mechanism of XXP on LUAD progression and stemness via lipid metabolism regulation.

UHPLC-MS/MS was used to analyze the chemical constituents of XXP. The effects of XXP on LUAD cell proliferation, migration, invasion, and stemness were evaluated using CCK-8, Transwell, and tumor sphere assays. A LUAD xenograft model confirmed XXP's anti-tumor effects. Transcriptomics, metabolomics, ELISA, qRT-PCR, and Western blot were used to investigate the underlying mechanisms. Kaplan-Meier (KM) survival analysis and stemness index scores were performed for LUAD patients based on the TCGA dataset. Statistical analyses were performed using Student's t-test, ANOVA, and KM survival analysis (p< 0.05 considered significant).

XXP inhibits LUAD progression in mouse and cell models by targeting lipid metabolism reprogramming. It suppresses FA synthesis, elongation, oxidation, and glycerophospholipid (GPL) metabolism while upregulating arachidonic acid (AA) metabolism. Mechanistic studies revealed that XXP attenuates tumor stemness by inhibiting PLA2G4A (cPLA2), lowering AA release, and disrupting SMO/GLI1/SOX2 signaling, an effect also observed with the cPLA2 inhibitor AACOCF3. KM analysis showed that higher PLA2G4A expression correlated with a worse 5-year prognosis in LUAD (p = 0.0047). The low GPL/high AA group (consistent with XXP's metabolic pattern) had better survival (p = 0.0028) and a lower stemness index (p< 0.0001) than the high GPL/low AA unrelated group.

Xingxiao Pill modulates GPL and AA metabolism and downregulates the PLA2G4A (cPLA2)-AA/SMO/GLI1/SOX2 axis. Through this mechanism, XXP effectively inhibits tumor growth and stemness by targeting lipid metabolism.

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.

Intercellular communication is an essential hallmark of multicellular organisms for their development and adult tissue homeostasis. Over the past two decades, attention has been focused on communication mechanisms based on various membrane structures, as illustrated by the burst of scientific literature in the field of extracellular vesicles (EVs). These lipid bilayer-bound nano- or microparticles, as vehicle-like devices, act as regulators in various biological and physiological processes. When EVs are internalized by recipient cells, their membrane and cytoplasmic cargoes can interfere with cellular activities, affecting pathways that regulate cell proliferation, differentiation, and migration. In cancer, EVs can transfer oncogenic factors, stimulate neo-angiogenesis and immunosuppression, reprogram stromal cells, and confer drug resistance traits, thereby remodeling the surrounding microenvironment. Although the mechanisms underlying EV biogenesis and uptake are now better understood, little is known about the spatiotemporal mechanism(s) of their actions after internalization. In this respect, we have shown that a fraction of endocytosed EVs reaches the nuclear compartment via the VOR (VAP-A-ORP3-Rab7) complex-mediated docking of late endosomes to the outer nuclear membrane in the nucleoplasmic reticulum, positioning and facilitating the transfer of EV cargoes into the nucleoplasm via nuclear pores. Here, we highlight the EV heterogeneity, the cellular pathways governing EV release and uptake by donor and recipient cells, respectively, and focus on a novel intracellular pathway leading to the nuclear transfer of EV cargoes. We will discuss how to intercept it, which could open up new avenues for clinical applications in which EVs and other small extracellular particles (e.g., retroviruses) are implicated.

Fatty acids (FAs) have various functions on cell regulation considering their abundant types and metabolic pathways. In addition, the relation between FA and other nutritional metabolism makes their functions more complex. As the first place for diet-derived FA metabolism, intestine is significantly influenced despite lack of clear conclusions due to the inconsistent findings. In this review, we discuss the regulation of fatty acid metabolism on the fate of intestinal stem cells in homeostasis and disorders, and also focus on the intestinal tumor development and treatment from the aspect of gut microbiota-epithelium-immune interaction. We summarize that the balances between FA oxidation and glycolysis, between oxidative phosphorylation and ketogenesis, between catabolism and anabolism, and the specific roles of individual FA types determine the diverse effects of intestinal FA metabolism in different cases. We hope this will inspire further dissection and suggest precise dietary/metabolic intervention for different demands related to intestinal health.

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

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

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

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

Application of machine learning (ML) on cancer-specific pharmacogenomic datasets shows immense promise for identifying predictive response biomarkers to enable personalized treatment. We introduce CAN-Scan, a precision oncology platform, which applies ML on next-generation pharmacogenomic datasets generated from a freeze-viable biobank of patient-derived primary cell lines (PDCs). These PDCs are screened against 84 Food and Drug Administration (FDA)-approved drugs at clinically relevant doses (Cmax), focusing on colorectal cancer (CRC) as a model system. CAN-Scan uncovers prognostic biomarkers and alternative treatment strategies, particularly for patients unresponsive to first-line chemotherapy. Specifically, it identifies gene expression signatures linked to resistance against 5-fluorouracil (5-FU)-based drugs and a focal copy-number gain on chromosome 7q, harboring critical resistance-associated genes. CAN-Scan-derived response signatures accurately predict clinical outcomes across four independent, ethnically diverse CRC cohorts. Notably, drug-specific ML models reveal regorafenib and vemurafenib as alternative treatments for BRAF-expressing, 5-FU-insensitive CRC. Altogether, this approach demonstrates significant potential in improving biomarker discovery and guiding personalized treatments.

Colorectal cancer (CRC) represents a significant global health burden, with chemotherapy resistance representing a significant challenge to effective treatment. SEC23A, a core component of the COPII vesicle trafficking system, is of critical importance with regard to protein transport and cellular homeostasis. Nevertheless, its function in CRC progression and chemoresistance remains uncertain. The present study investigates the correlation between SEC23A expression and sensitivity to 5-fluorouracil (5-FU), a widely used chemotherapeutic agent, with particular emphasis on ER stress-induced apoptosis.

A bioinformatic analysis was conducted to evaluate SEC23A expression in CRC and its association with patient prognosis. Chemotherapy sensitivity was predicted using GDSC data and validated experimentally using CRC cell lines with manipulated SEC23A expression. In order to explore the role of SEC23A in acquired drug resistance, patient-derived xenograft (PDX) models and 5-FU-resistant cell lines were employed. Apoptosis assays, cell cycle analysis, and ER stress modulation experiments were performed to elucidate the underlying mechanisms.

SEC23A expression was significantly reduced in CRC samples compared to normal tissues. This reduction was linked to a poorer prognosis, including both overall and disease-specific survival. A correlation was observed between low SEC23A expression and increased resistance to 5-FU, as evidenced by both bioinformatic predictions and in vitro experiments. In PDX models, metastatic lesions exhibited decreased SEC23A expression following 5-FU treatment in comparison to primary tumors. Overexpression of SEC23A in 5-FU-resistant cell lines restored sensitivity to the drug and increased apoptosis. Bioinformatic and experimental analyses revealed a robust correlation between SEC23A and ER stress-related apoptotic pathways. Elevated expression of SEC23A was observed to facilitate the accumulation of misfolded proteins in response to 5-FU treatment, which in turn resulted in increased ER stress and apoptosis.

SEC23A plays a crucial role in modulating the sensitivity of CRC cells to 5-FU by regulating ER stress-induced apoptosis. Its downregulation contributes to chemoresistance, indicating that SEC23A may serve as a prognostic marker and therapeutic target in CRC. Strategies aimed at upregulating SEC23A or enhancing ER stress may provide new avenues for overcoming chemoresistance and improving treatment outcomes for CRC patients.

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

Metastasis is the primary cause of cancer mortality. It is responsible for 90% of all cancer-related deaths. Intercellular communication is a crucial feature underlying cancer metastasis and progression. Cancerous tumors secrete membrane-derived small extracellular vesicles (30-150 nm) into their extracellular milieu. These tiny organelles, known as exosomes, facilitate intercellular communication by transferring bioactive molecules. These exosomes harbor different cargos, such as proteins, nucleic acids, and lipids, that mediate multifaceted functions in various oncogenic processes. Of note, the amount of lipids in exosomes is multifold higher than that of other cargos. Most studies have investigated the role of exosomes' protein and nucleic acid content in various oncogenic processes, while the role of lipid cargo in cancer pathophysiology remains largely obscure.

We conducted an extensive literature review on the role of exosomes and lipids in cancer progression, specifically addressing the topic of exosomal lipids and their involvement in cancer metastasis and progression.

This review aims to shed light on the lipid contents of exosomes in cancer metastasis. In this context, the role of exosomal lipids in signaling pathways, immunomodulation, and energy production for cancer cell survival provides insights into overcoming cancer progression and metastasis.

With few viable treatment options, glioblastoma (GBM) is still one of the most aggressive and deadly types of brain cancer. Recent developments in lipidomics have demonstrated the potential of lipid metabolism as a therapeutic target in GBM. The thorough examination of lipids in biological systems, or lipidomics, is essential to comprehending the changed lipid profiles found in GBM, which are linked to the tumor's ability to grow, survive, and resist treatment. The use of lipidomics in drug delivery and discovery is examined in this study, focusing on how it may be used to find new biomarkers, create multi-target directed ligands, and improve drug delivery systems. We also cover the use of FDA-approved medications, clinical trials that use lipid-targeted medicines, and the integration of lipidomics with other omics technologies. This study emphasizes lipidomics as a possible tool in developing more effective treatment methods for GBM by exploring various lipid-centric techniques.

Colorectal cancer (CRC), an emerging public health concern, is one of the leading causes of cancer morbidity and mortality worldwide. An increasing body of evidence shows that dysfunction in metabolic reprogramming is a crucial characteristic of CRC progression. Specifically, metabolic reprogramming abnormalities in glucose, glutamine and lipid metabolism provide the tumour with energy and nutrients to support its rapid cell proliferation and survival. More recently, microRNAs (miRNAs) appear to be involved in the pathogenesis of CRC, including regulatory roles in energy metabolism. In addition, it has been revealed that dysbiosis in CRC might play a key role in impairing the host metabolic reprogramming processes, and while the exact interactions remain unclear, the link may lie with miRNAs. Hence, the aims of the current review include first, to delineate the metabolic reprogramming abnormalities in CRC; second, to explain how miRNAs mediate the aberrant regulations of CRC metabolic pathways; third, linking miRNAs with metabolic abnormalities and dysbiosis in CRC and finally, to discuss the roles of miRNAs as potential biomarkers.

Drug resistance is an inherent challenge during cancer chemotherapy. Cancer cells favor fatty acid metabolism through metabolic reprogramming to achieve therapeutic resistance. However, an effective approach to overcoming the switch from glycolysis-dependent to fatty acid beta-oxidation-dependent anabolic and energy metabolism remains elusive. Here, we developed a macromolecular drug (folate-polySia, FpSA) to induce the extracellular microcalcification of cervical cancer cells with cisplatin resistance. Microcalcification attenuated the uptake of fatty acids and the beta-oxidation of fatty acids by mitochondrial dysfunction but boosted the glycolysis pathway. Consequently, cotreatment with Pt and FpSA inhibited cisplatin-resistant tumor growth and improved tumor-bearing mice's survival rates, indicating that FpSA switched fatty acid metabolism to glycolysis to sensitize cisplatin-resistant cells further. Taken together, cancer cell calcification induced by FpSA provides a reprogramming metabolic strategy for the treatment of chemotherapy-resistant tumors.

Membrane contact sites (MCS) are specialized regions where organelles are closely interconnected through membrane structures, facilitating the transfer and exchange of ions, lipids, and other molecules. This proximity enables a synergistic regulation of cellular homeostasis and functions. The formation and maintenance of these contact sites are governed by specific proteins that bring organelle membranes into close apposition, thereby enabling functional crosstalk between cellular compartments. In eukaryotic cells, lipids are primarily synthesized and metabolized within distinct organelles and must be transported through MCS to ensure proper cellular function. Consequently, MCS act as pivotal platforms for lipid synthesis and trafficking, particularly in cancer cells and immune cells within the tumor microenvironment, where dynamic alterations are critical for maintaining lipid homeostasis. This article provides a comprehensive analysis of how these cells exploit membrane contact sites to modulate lipid synthesis, metabolism, and transport, with a specific focus on how MCS-mediated lipid dynamics influence tumor progression. We also examine the differences in MCS and associated molecules across various cancer types, exploring novel therapeutic strategies targeting MCS-related lipid metabolism for the development of anticancer drugs, while also addressing the challenges involved.

Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is a multifaced enzyme with a wide spectrum of substrates, from lipids through waxes to retinoids, which makes it an interesting therapeutic target. DGAT1 inhibitors are currently at various stages of preclinical and clinical trials, mostly related to metabolic diseases. Interestingly, in recent years, a growing amount of research has shown the influence of DGAT1 on immune cell metabolism and functions, highlighting its important role during infections and tumorigenesis. In this review, we aim to elucidate the potential immunomodulatory effect of DGAT1 in physiological and pathological conditions.

The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aimed to determine the significance of diacyltransferases (diacylglycerol o-acyltransferases 1 and 2 [DGAT1/2]), responsible for LDs biogenesis, in obesity-mediated colonic tumorigenesis.

Human colon cancer samples, colon cancer cells, colonospheres, and ApcMin/+ colon cancer mouse model on a high-fat diet were employed. For DGAT1/2 inhibition, enzymatic inhibitors and small interfering RNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analyses of CUT&RUN and RNA sequencing data were performed.

DGAT1/2 levels in human colon cancer tissue are significantly elevated with disease severity and obesity (vs normal). Their levels are increased in human colon cancer cells (vs nontransformed) and further enhanced by fatty acids prevalent in obesity; augmented DGAT2 expression is MYC-dependent. Inhibition of DGAT1/2 improves FOXO3 activity by attenuating PI3K, resulting in reduced MYC-dependent DGAT2 expression and accumulation of LDs, suggesting feedback. This inhibition attenuated growth in colon cancer cells and colonospheres via FOXO3/p27kip1 cell cycle arrest and reduced colonic tumors in ApcMin/+ mice on a high-fat diet. Transcriptomic analysis revealed that DGAT1/2 inhibition targeted metabolic and tumorigenic pathways in human colon cancer and colon cancer crypts, stratifying human colon cancer samples from normal. Further analysis revealed that this inhibition is predictive of advanced disease-free state and survival in patients with colon cancer.

This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, providing a platform for future development of effective treatments for patients with colon cancer.

Extracellular membrane vesicles (EVs) offer promising values in various medical fields, e.g., as biomarkers in liquid biopsies or as native (or bioengineered) biological nanocarriers in tissue engineering, regenerative medicine and cancer therapy. Based on their cellular origin EVs can vary considerably in composition and diameter. Cell biological studies on mammalian prominin-1, a cholesterol-binding membrane glycoprotein, have helped to reveal new donor membranes as sources of EVs. For instance, small EVs can originate from microvilli and primary cilia, while large EVs might be produced by transient structures such as retracting cellular extremities of cancer cells during the mitotic rounding process, and the midbody at the end of cytokinesis. Here, we will highlight the various subcellular origins of prominin-1+ EVs, also called prominosomes, and the potential mechanism(s) regulating their formation. We will further discuss the molecular and cellular characteristics of prominin-1, notably those that have a direct effect on the release of prominin-1+ EVs, a process that might be directly implicated in donor cell reprogramming of stem and cancer stem cells. Prominin-1+ EVs also mediate intercellular communication during embryonic development and adult homeostasis in healthy individuals, while disseminating biological information during diseases.

Chronic drug treatment can alter the lipidome of cancer cells, potentially leading to significant biological changes, such as drug resistance or increased tumor aggressiveness. This study examines the lipidome profiles of four human colorectal cancer (CRC) cell lines, comparing treatment-naïve cells with the same cells after chronic exposure to a clinically used combination therapy (FOLFOXIRI: folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan). Lipidomic profiling was obtained with untargeted liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). For data deconvolution and to interpret the multifactorial dataset generated, Analysis of Variance Multiblock Orthogonal Partial Least Squares (AMOPLS) was used. Our results indicate specific shifts in triglycerides (TGs), sphingolipids, and phospholipids in CRC cells resistant to FOLFOXIRI. The overall shift in TGs, phosphatidylcholine, and cholesteryl ester species was notably linked to FOLFOXIRI resistance (-R) in SW620 cells, whereas an increased abundance of phospholipids, mainly hexosylceramide and sphingomyelin, was present in the signatures of HCT116-R, LS174T-R, and DLD1-R cells. These altered lipid species may serve as potential prognostic markers in CRC following chemotherapy. Furthermore, lipid-targeting therapies aimed at reprogramming the lipid profiles of drug-resistant cells could play a crucial role in restoring drug sensitivity and improving patient survival.

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long-chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpassSM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose- and time-dependent manner. RNA-sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma.

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

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the PDAC microenvironment. The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. Our data suggested that much like hypoxia, CLS in the tumor microenvironment could promote PDAC tumor growth and metastasis through upregulating anabolic metabolism of nucleotides and lipids.

The 5-fluorouracil (5-FU)-based chemotherapy regimen is a primary strategy for treating pancreatic cancer (PC). However, challenges related to 5-FU resistance persist. Investigating the mechanisms of 5-FU resistance and identifying a clinically viable therapeutic strategy are crucial for improving the prognosis of PC. Here, through clinical samples analysis, we found that the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in mevalonate metabolism, is negatively correlated with the efficacy of 5-FU treatment. There is a significant correlation between HMGCR and the pyroptosis marker gasdermin D (GSDMD), and the HMGCR inhibitor simvastatin can significantly inhibit the activation of pyroptosis signaling. The exogenous addition of geranylgeranyl pyrophosphate (GGPP), a key metabolite of the mevalonate pathway, can significantly reduce sensitivity to 5-FU, and simvastatin combined with 5-FU demonstrates a strong synergistic effect. Furthermore, in organoid models and genetically engineered mice with spontaneous PC, the combination of simvastatin and 5-FU significantly inhibits tumor growth. In conclusion, our study reveals the critical role of the mevalonate pathway in 5-FU resistance and proposes a clinically feasible combination therapy strategy.

Reactive oxygen species (ROS) are a group of highly active molecules produced by normal cellular metabolism and play a crucial role in the human body. In recent years, researchers have increasingly discovered that ROS plays a vital role in the progression of chronic inflammation and tumor metastasis. The inflammatory tumor microenvironment established by chronic inflammation can induce ROS production through inflammatory cells. ROS can then directly damage DNA or indirectly activate cellular signaling pathways to promote tumor metastasis and development, including breast cancer, lung cancer, liver cancer, colorectal cancer, and so on. This review aims to elucidate the relationship between ROS, chronic inflammation, and tumor metastasis, explaining how chronic inflammation can induce tumor metastasis and how ROS can contribute to the evolution of chronic inflammation toward tumor metastasis. Interestingly, ROS can have a "double-edged sword" effect, promoting tumor metastasis in some cases and inhibiting it in others. This article also highlights the potential applications of ROS in inhibiting tumor metastasis and enhancing the precision of tumor-targeted therapy. Combining ROS with nanomaterials strategies may be a promising approach to enhance the efficacy of tumor treatment.

Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001-0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment.

Colorectal cancer (CRC) is the third most incident and the second most lethal malignant tumor. Despite the recognized association between obesity and CRC, further clarification is necessary regarding the lipids that are overexpressed during the development of CRC. In this scenario, the combination of metabolomics and a three-dimensional (3D) co-culture model involving CRC tumor cells and lipids can enhance the knowledge of energy metabolism modifications at the cross-talk between colorectal cancer and adipocytes. This study aimed to screen potential metabolites in the three dimensional (3D) co-culture of CRC and adipocytes by investigating the metabolome composition of this co-culture released into the extracellular space, which is known as the secretome.

Pre-adipocyte cells (3T3-L1), human colon carcinoma (HT-29), and the 3D co-culture (3T3-L1 + HT-29) were cultured for the secretome obtention. Then, ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was employed to analyze the metabolomics of each secretome.

Overall, 3.731 molecules were detected independent of the cell culture. When comparing the three cultures, 105 molecules presented a statistically significant difference in abundance between groups. Among these molecules, 16 were identified, with a particular emphasis on six lipids (PG 20:0, octadecenal, 3-Hydroxytetracosanoyl-CoA, 9,10-dihydroxy-octadecenoic acid, palmitoleic acid, and PA 18:4) and one amino acid derivative (acetylglutamic acid), which presented significant scores during the partial least-squares discriminant analysis (PLS-DA).

Although it is too early to determine the possible impact of such molecules in a CRC microenvironment, these results open new avenues for further studies on the energy metabolism at the cross-talk of colorectal cancer adipocytes.

Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8+ T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6+ Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.

Lipid droplet (LD) accumulation is one of the features in various tumors, whereas the significance of LD accumulation in pancreatic cancer progression remains unclear under chemotherapeutic condition. Since chemoresistance towards gemcitabine (GEM) is an obstacle for clinical therapy of pancreatic cancer, we sought to investigate the contribution of LD accumulation to GEM resistance. Herein, triacsin C (an inhibitor of LD production) dampened the proliferation, migration, and invasion of pancreatic cancer cells. The inhibition of LD accumulation induced by triacsin C or silencing of perilipin 2 (a marker of LD) sensitized cells to GEM treatment. Next, 75 paraffin-embedded samples and 5 pairs of frozen samples from pancreatic cancer patients were obtained for the detection of lysophosphatidylcholine acyltransferase 2 (LPCAT2; a LD-located enzyme contributing phosphatidylcholine synthesis) expression. The results revealed that LPCAT2 was upregulated in pancreatic cancer tissues, and its expression was correlated with clinical parameters and the basal LD content of cancer cell lines. Loss of LPCAT2 repressed the LD accumulation, GEM resistance, and cell motility. The enhancement of chemotherapy sensitivity was further confirmed in a xenograft model of mice in vivo. The carcinogenesis role of LPCAT2 was at least partly mediated by the LD accumulation. Then, signal transducer and activator of transcription 5B (STAT5B) activated the transcription of LPCAT2. Both LPCAT2 downregulation and triacsin C reversed the STAT5B-induced potentiation of malignant phenotypes in pancreatic cancer cells. In conclusion, LPCAT2-mediated lipid droplet production supported pancreatic cancer chemoresistance and cell motility, which was triggered by STAT5B.

We conducted an extensive, sex-oriented real-world data analysis to explore the impact and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (coxibs) on cancer treatment outcomes. This is particularly relevant given the role of the COX-2/PGE2 pathway in tumor cell resistance to chemotherapy and radiotherapy.

The study applied a retrospective cohort design utilizing the TriNetX research database consisting of patients receiving cancer treatment in 2008-2022. The treated cohorts included patients who were prescribed with coxibs, aspirin or ibuprofen, while individuals in the control cohort did not receive these medicines during their cancer treatment. A 1:1 propensity score matching technique was used to balance the baseline characteristics in the treated and control cohorts. Then, Cox proportional hazards regression and logistic regression were applied to assess the mortality and morbidity risks among patient cohorts in a 5-year follow-up period.

Use of coxibs (HR, 0.825; 95% CI 0.792-0.859 in females and HR, 0.884; 95% CI 0.848-0.921 in males) and ibuprofen (HR, 0.924; 95% CI 0.903-0.945 in females and HR, 0.940; 95% CI 0.917-0.963 in males) were associated with improved survival. Female cancer patients receiving aspirin presented increased mortality (HR, 1.078; 95% CI 1.060-1.097), while male cancer patients also had improved survival when receiving aspirin (HR, 0.966; 95% CI 0.951-0.980). Cancer subtype specific analysis suggests coxibs and ibuprofen correlated with survival, though ibuprofen and aspirin increased emergency department visits' risk. Secondary analyses, despite limited by small cohort sizes, suggest that COX inhibition post-cancer diagnosis may benefit patients with specific cancer subtypes.

Selective COX-2 inhibition significantly reduced mortality and emergency department visit rates. Further clinical trials are needed to determine the optimal conditions for indication of coxibs as anti-inflammatory adjuvants in cancer treatment.

The involvement of immune cells in colorectal cancer (CRC) and their interplay with metabolic disorders are yet to be fully elucidated. This study examines how peripheral immune cells, inferred genetically, affect CRC and investigates the intermediary roles of metabolites.

We employed a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal influence of immune cells on CRC. Additionally, a two-step MR strategy was utilized to pinpoint potential metabolites that mediate this effect. Our analysis incorporated data from genome-wide association studies (GWAS), involving 731 immune cell types, 1,400 metabolites, and CRC outcomes. The primary method of analysis was randomized inverse variance weighting (IVW), supported by MR-Egger, weighted median, simple mode, and weighted mode analyses. Sensitivity checks were conducted using Cochran's Q test, MR-PRESSO test, MR-Egger regression intercept, and leave-one-out analysis.

The study identified 23 immune cell types and 17 metabolites that are causally linked to CRC. Our mediation analysis highlighted that nine metabolites act as intermediaries in the relationship between nine specific immune cells and CRC risk. Notably, The ratios of Adenosine 5'-monophosphate (AMP) to aspartate and Retinol (Vitamin A) to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) were found to concurrently mediate the promoting effects of Myeloid DC %DC and BAFF-R on B cells in colorectal cancer (CRC). Moreover, iminodiacetate (IDA) was found to mediate the protective effect of CD14+ CD16- monocytes on CRC, contributing 11.8% to this mediation. In contrast, IDA was also seen to decrease the protective effect of IgD+ CD38br %B cells on CRC risk, with a mediation effect proportion of -10.4%.

This study delineates a complex network involving immune cells, metabolites, and CRC, suggesting a multifaceted pathophysiological interaction. The identified causal links and mediation pathways underscore potential therapeutic targets, providing a foundation for interventions aimed at modulating immune responses to manage CRC.

Glycerophospholipids, a primary component of cellular membranes, play important structural and functional roles in cells. In the remodelling pathway (Lands' cycle), the concerted actions of phospholipase As and lysophospholipid acyltransferases (LPLATs) contribute to the incorporation of diverse fatty acids in glycerophospholipids in an asymmetric manner, which differ between cell types. In this study, the role of LPLATs in osteoblastic differentiation of C2C12 cells was investigated. Gene and protein expression levels of lysophosphatidylcholine acyltransferase 2 (LPCAT2), one of the LPLATs, increased during osteoblastic differentiation in C2C12 cells. LPCAT2 knockdown in C2C12 cells downregulated the expression of osteoblastic differentiation markers and the number and size of lipid droplets (LDs) and suppressed the phosphorylation of Smad1/5/9. In addition, LPCAT2 knockdown inhibited Snail1 and the downstream target of Runx2 and vitamin D receptor (VDR). These results suggest that LPCAT2 modulates osteoblastic differentiation in C2C12 cells through the bone morphogenetic protein (BMP)/Smad signalling pathway.

Cancer is closely related to lipid metabolism, with the tumor microenvironment (TME) containing numerous lipid metabolic interactions. Cancer cells can bidirectionally interact with immune and stromal cells, the major components of the TME. This interaction is primarily mediated by fatty acids (FAs), cholesterol, and phospholipids. These interactions can lead to various physiological changes, including immune suppression, cancer cell proliferation, dissemination, and anti-apoptotic effects on cancer cells. The physiological modulation resulting from this lipid metabolism-associated crosstalk between cancer cells and immune/stromal cells provides valuable insights into cancer prognosis. A comprehensive literature review was conducted to examine the function of the bidirectional lipid metabolism interactions between cancer cells and immune/stromal cells within the TME, particularly how these interactions influence cancer prognosis. A novel autophagy-extracellular vesicle (EV) pathway has been proposed as a mediator of lipid metabolism interactions between cancer cells and immune cells/stromal cells, impacting cancer prognosis. As a result, different forms of lipid metabolism interactions have been described as being linked to cancer prognosis, including those mediated by the autophagy-EV pathway. In conclusion, understanding the bidirectional lipid metabolism interactions between cancer cells and stromal/immune cells in the TME can help develop more advanced prognostic approaches for cancer patients.

Recent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood.

We conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism.

We identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion.

Our study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.

The regular overconsumption of high-energy food (rich in lipids and sugars) results in elevated nutrient absorption in intestine and consequently excessive accumulation of lipids in many organs e.g.: liver, adipose tissue, muscles. In the long term this can lead to obesity and obesity-associated diseases e.g. type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease, inflammatory bowel disease (IBD). In the presented paper based on RI data we have proved that Raman maps can be used successfully for subcellular structures visualization and analysis of fatty acids impact on morphology and chemical composition of human colon single cells - normal and cancer. Based on Raman data we have investigated the changes related to endoplasmic reticulum, mitochondria, lipid droplets and nucleus. Analysis of ratios calculated based on Raman bands typical for proteins (1256, 1656 cm-1), lipids (1304, 1444 cm-1) and nucleic acids (750 cm-1) has confirmed for endoplasmic reticulum the increased activity of this organelle in lipoproteins synthesis upon FAs supplementation; for LDs the changes of desaturation of accumulated lipids with the highest unsaturation level for CaCo-2 cells upon EPA supplementation; for mitochondria the stronger effect of FAs supplementation was observed for CaCo-2 cells confirming the increased activity of this organelle responsible for energy production necessary for tumor development; the weakest impact of FAs supplementation was observed for nucleus for both types of cells and both types of acids. Fluorescence imaging was used for the investigations of changes in LDs/ER morphology. Our measurements have shown the increased area of LDs/ER for CaCo-2 cancer cells, and the strongest effect was noticed for CaCo-2 cells upon EPA supplementation. The increased participation of lipid structures for all types of cells upon FAs supplementation has been confirmed also by AFM studies. The lowest YM values have been observed for CaCo-2 cells including samples treated with FAs.

We implemented a multimodal set of functional imaging techniques optimized for deep-tissue imaging to investigate how cancer cells invade surrounding tissues and how their physiological properties change in the process. As a model for cancer invasion of the extracellular matrix, we created 3D spheroids from triple-negative breast cancer cells (MDA-MB-231) and non-tumorigenic breast epithelial cells (MCF-10A). We analyzed multiple hallmarks of cancer within the same spheroid by combining a number of imaging techniques, such as metabolic imaging of NADH by Fluorescence Lifetime Imaging Microscopy (NADH-FLIM), hyperspectral imaging of a solvatochromic lipophilic dye (Nile Red) and extracellular matrix imaging by Second Harmonic Generation (SHG). We included phasor-based bioimage analysis of spheroids at three different time points, tracking both morphological and biological properties, including cellular metabolism, fatty acids storage, and collagen organization. Employing this multimodal deep-imaging framework, we observed and quantified cancer cell plasticity in response to changes in the environment composition.

Epigenetic regulation established during development to maintain patterns of transcriptional expression and silencing for metabolism and other fundamental cell processes can be reprogrammed in cancer, providing a molecular mechanism for persistent alterations in phenotype. Metabolic deregulation and reprogramming are thus an emerging hallmark of cancer with opportunities for molecular classification as a critical preliminary step for precision therapeutic intervention. Yet, acquisition of therapy resistance against most conventional treatment regimens coupled with tumor relapse, continue to pose unsolved problems for precision healthcare, as exemplified in breast cancer where existing data informs both cancer genotype and phenotype. Furthermore, epigenetic reprograming of the metabolic milieu of cancer cells is among the most crucial determinants of therapeutic resistance and cancer relapse. Importantly, subtype-specific epigenetic-metabolic interplay profoundly affects malignant transformation, resistance to chemotherapy, and response to targeted therapies. In this review, we therefore prismatically dissect interconnected epigenetic and metabolic regulatory pathways and then integrate them into an observable cancer metabolism-therapy-resistance axis that may inform clinical intervention. Optimally coupling genome-wide analysis with an understanding of metabolic elements, epigenetic reprogramming, and their integration by metabolic profiling may decode missing molecular mechanisms at the level of individual tumors. The proposed approach of linking metabolic biochemistry back to genotype, epigenetics, and phenotype for specific tumors and their microenvironment may thus enable successful mechanistic targeting of epigenetic modifiers and oncometabolites despite tumor metabolic heterogeneity.