The exploration of therapeutic targets in neuroblastoma (NB), which needs more attempts, can benefit patients with high-risk NB. Based on metabolomic and transcriptomic data in mediastinal NB tissues, we found that the content of long-chain acylcarnitine (LCAC) was increased and positively associated with leptin expression in advanced NB. Leptin over-expression forced naïve CD4+ T cells to differentiate into Treg cells instead of Th17 cells, which benefited from NB cell proliferation, migration, and drug resistance. Mechanically, leptin in NB cells blunted the activity of carnitine palmitoyltransferase 2 (CPT2), the key enzyme for LCAC catabolism, by inhibiting sirtuin 3-mediated CPT2 deacetylation, which depresses oxidative phosphorylation (OXPHOS) for energy supply and increases lactic acid (LA) production from glycolysis to modulate CD4+ T cell differentiation. These findings highlight that excess leptin contributes to lipid metabolism dysfunction in NB cells and subsequently misdirects CD4+ T cell differentiation in tumor micro-environment (TME), indicating that targeting leptin could be a therapeutic strategy for retarding NB progression.

Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells that orchestrate cancer initiation, progression, metastasis, and therapeutic resistance. Despite advances in conventional therapies, the persistence of CSCs remains a major obstacle to achieving cancer eradication. Nanomedicine-based approaches have emerged for precise CSC targeting and elimination, offering unique advantages in overcoming the limitations of traditional treatments. This review systematically analyzes recent developments in nanomedicine for CSC-targeted therapy, emphasizing innovative nanomaterial designs addressing CSC-specific challenges. We first provide a detailed examination of CSC biology, focusing on their surface markers, signaling networks, microenvironmental interactions, and metabolic signatures. On this basis, we critically evaluate cutting-edge nanomaterial engineering designed to exploit these CSC traits, including stimuli-responsive nanodrugs, nanocarriers for drug delivery, and multifunctional nanoplatforms capable of generating localized hyperthermia or reactive oxygen species. These sophisticated nanotherapeutic approaches enhance selectivity and efficacy in CSC elimination, potentially circumventing drug resistance and cancer recurrence. Finally, we present an in-depth analysis of current challenges in translating nanomedicine-based CSC-targeted therapies from bench to bedside, offering critical insights into future research directions and clinical implementation. This review aims to provide a comprehensive framework for understanding the intersection of nanomedicine and CSC biology, contributing to more effective cancer treatment modalities.

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

Fatty acid oxidation (FAO) denotes the mitochondrial aerobic process responsible for breaking down fatty acids (FAs) into acetyl-CoA units. This process holds a central position in the cancer metabolic landscape, with certain tumor cells relying primarily on FAO for energy production. Over the past decade, mounting evidence has underscored the critical role of FAO in various cellular processes such as cell growth, epigenetic modifications, tissue-immune homeostasis, cell signal transduction, and more. FAO is tightly regulated by multiple evolutionarily conserved mechanisms, and any dysregulation can predispose to cancer development. In this view, we summarize recent findings to provide an updated understanding of the multifaceted roles of FAO in tumor development, metastasis, and the response to cancer therapy. Additionally, we explore the regulatory mechanisms of FAO, laying the groundwork for potential therapeutic interventions targeting FAO in cancers within the metabolic landscape.

Pancreatic cancer is a highly aggressive gastrointestinal tumor with limited treatment options, such as surgery and chemotherapy. Thus, further research into its pathogenesis and new treatments is necessary.

Fluorescence-activated cell sorting was employed to sort pancreatic cancer stem cells (PCSCs). Sphere formation assays and Cell Counting Kit-8 (CCK-8) assays were conducted to assess stemness and proliferation capacity. Quantitative real-time PCR and Western blot analysis were employed to assess gene expression levels. Furthermore, immunofluorescence microscopy and chromatin immunoprecipitation assays were conducted to examine alterations in signaling pathways and gene expression.

Quercetin and gemcitabine may inhibit PANC-1 cells and PCSCs by affecting energy metabolism. Chromatin immunoprecipitation assays revealed an interaction between STAT3 and CPT1B in PCSCs. Quercetin and gemcitabine might affect energy metabolism by inhibiting STAT3 and CPT1B. Manipulating STAT3 expression (overexpression plasmids and siRNA knockdown) altered CPT1B mRNA and protein expression. Although acetyl-CoA reversed the quercetin- and gemcitabine-induced expression of N-cadherin, DECR1, and ALDH, it had minimal influence on CPT1B and STAT3 levels.

Quercetin inhibits the expression of CPT1B via the STAT3 signaling pathway, affecting lipid metabolism and exerting antitumor effects. Furthermore, the combined administration of quercetin and gemcitabine exhibits enhanced therapeutic efficacy.

Breast cancer ranks among the most common cancers globally, with significant mortality rates in advanced stages. Despite progress in treatment, therapy resistance, particularly to radiotherapy, remains a major challenge. Radiosensitization offers a promising solution to enhance radiotherapy effectiveness. This approach specifically increases tumor cells' vulnerability to IR. Recent research has explored molecular targets and strategies to improve radiosensitivity in breast cancer. Examples include inhibiting DNA repair pathways, altering the TME, targeting signaling pathways, and using immunomodulators. These strategies not only amplify destructive effects of IR but may also reduce required radiation doses, thereby minimizing normal tissue injury. This review examines promising molecular targets and combination therapies to boost radiosensitivity in breast cancer. It also highlights recent advances in immune modulation, TME remodeling, targeted molecular therapy, and metabolic pathway targeting. These advancements offer insights into the future of radiosensitization research. By systematically analyzing these strategies, the article aims to provide a comprehensive understanding of radiosensitization's current state and future potential in breast cancer treatment.

Lysine demethylase 4D (KDM4D) and aberrant lipid metabolism are implicated in the development and progression of colitis-associated cancer (CAC). Moxibustion, a therapeutic approach in traditional Chinese medicine, can inhibit intestinal inflammation and improve the intestinal mucosa.

Mice were intraperitoneally injected with AOM, and three cycles of 3-2-2% DSS-free drinking water were administered to establish a CAC mouse model. Moxibustion and KDM4D inhibitor 5-c-8HQ intervention were performed for 30 days after modeling was completed. IHC staining was used to observe the expression of the nuclear-associated antigen Ki67 (Ki67), proliferating cell nuclear antigen (PCNA), and IL-33 in the colon. The expression of colon KDM4D and β-Catenin was observed by immunofluorescence staining and RT‒qPCR. LC‒MS pseudotargeted metabolomic sequencing was used to semiquantitatively detect the expression levels of lipids.

Moxibustion inhibited the proliferation of colon tumors in CAC mice, improved histopathology, and reduced the expression of PCNA and Ki67 in the colon. Using kdm4d knockout technology, it was initially confirmed that kdm4d is a key gene affecting CAC tumor proliferation. The inhibition of colon tumor proliferation in CAC mice by moxibustion is associated with the suppression of abnormal activation of the colon KDM4D/β-Catenin signaling pathway. LC-MS-targeted metabolomics revealed abnormal lipid metabolism in the colons of CAC mice. Moxibustion may affect the cholinergic metabolism pathway in the colon of CAC mice and regulate lipids such as sphingomyelin SM (d18:1/26:0) and triacylglycerol TAG58:7 (18:0). After kdm4d knockout, lipid disorders in the colons of CAC mice were partially restored. The kdm4d gene may be involved in the mechanism underlying the effect of moxibustion on lipid metabolism in the CAC colon.

Moxibustion inhibited the proliferation of colon tumors in CAC mice, inhibited the activation of the tumor-promoting signaling pathway KDM4D/β-Catenin, and improved lipid metabolism disorders in the colon, thus providing a promising strategy for the clinical adjuvant treatment of colorectal cancer.

The intersection of aberrant iron metabolism and the rapidly advancing field of immunotherapy has emerged as a critical focus in breast cancer (BRCA) therapeutics. Ferroptosis, a distinct form of iron-dependent cell death driven by lipid peroxidation, has garnered increasing attention for its pivotal role in cancer progression.

Utilizing extensive datasets from TCGA and GEO, this research extracted a wealth of biological data, including mRNA splicing indices, genomic aberrations, copy number variations (CNV), tumor mutational burden (TMB), and diverse clinical information. Through precise Lasso regression analysis, this research constructed a prognostic model that elucidates the molecular interactions of FRGs in BRCA. Concurrent co-expression network analyses were performed to explore the dynamic interplay between gene expression patterns and FRGs, revealing potential regulatory mechanisms.

This research analysis revealed significant overexpression of FRGs in high-risk BRCA samples, highlighting their prognostic relevance beyond traditional clinical parameters. GSVA identified immune response and cancer-related pathways as predominantly active in high-risk groups, suggesting ferroptosis as a central modulator within the tumor microenvironment. Notably, genes such as ACTL8, VGF, and CPLX2 emerged as markers of tumorigenesis, while IL33 and TP63 were identified as potential key regulators of cancer progression, each exhibiting distinct expression profiles across risk levels. Furthermore, this research incorporated gene correlations, CNV profiles, SNP arrays, and drug susceptibility analyses, contributing to the advancement of precision oncology.

The integration of bioinformatics and machine learning in this study underscores a strong correlation between FRG expression patterns and BRCA prognosis, affirming their potential as precise biomarkers for personalized immunotherapy.

The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.

The initiation and progression of clear cell renal cell carcinoma (ccRCC) are closely linked to significant metabolic alterations. Specifically, lipid metabolism alterations and their association with the high invasiveness in ccRCC require further investigation. After conducting RNA-sequencing (RNA-seq), we discovered that Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta (HADHB) was significantly downregulated in the highly invasive ccRCC cell line. It was found that the expression of HADHB in ccRCC tumor tissues was lower than that in paracancer tissues, which is associated with poor patient prognosis. Subsequently, we confirmed that highly invasive ccRCC exhibited an increased lipid accumulation due to the suppression of mitochondrial fatty acid transport and enhanced conversion of fatty acids to triglycerides within cancer cells. Specifically, the downregulation of HADHB inhibited mitochondrial fatty acid β-oxidation (FAO) in cancer cells, leading to partial impairment of mitochondrial function and decreased ATP production. However, this trade-off involving the reduction of a high-yield ATP production conferred an advantage by reducing reactive oxygen species (ROS) generation within cancer cells, thereby protecting them from oxidative stress and enhancing their invasive potential. Furthermore, the downregulation of HADHB promoted epithelial-mesenchymal transition (EMT) and angiogenesis in cancer cells, accelerating the progression of ccRCC and endowing ccRCC cells with metastatic capabilities.

Glioblastoma is the most aggressive primary brain tumor in adults. The prognosis is still very poor with a median survival time less than a year. A growing body of data supports the role for fatty acid oxidation (FAO) in the aggressive behavior of glioblastoma. We have previously shown that meldonium, an orally active compound that impairs FAO, caused significant growth reduction of glioblastoma in mice. Here, we report three cases of experimental meldonium-containing therapy in end-stage recurrent glioblastoma patients.

Three end-stage glioblastoma patients, who had second relapse tumor progression after standard of care therapy, received 500 mg meldonium twice a day on the top of the existing therapy regimen. Tolerability and treatment outcomes were monitored.

Meldonium was well tolerated by all three patients. One patient experienced long-term growth arrest and maintained clinically stable disease status, currently 24 months into treatment with meldonium. In contrast, the other two patients passed away.

The case reports presented here suggest good tolerability and the potential for meldonium to improve outcome in glioblastoma patients. Controlled clinical trials need to follow to evaluate systematically possible benefits from the integration of meldonium into standard glioblastoma treatment protocols.

We conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC).

We aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC.

Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition.

MALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice.

Our work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.

The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restores anti-tumor immunity and re-sensitizes the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlates with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.

Glioblastoma (GBM) is the most lethal type of brain tumor. Recent studies have indicated that cellular senescence-targeted therapy is a promising approach for cancer treatment. However, the underlying mechanisms remain to be clarified. In this study, 101 unique combinations of 10 machine learning algorithms were used to construct prognostic models based on cellular senescence-related genes (CSRGs). We developed the CSRG signature (CSRGS) using machine learning models that exhibited optimal performance. GBM samples were stratified into high- and low-CSRGS groups based on CSRGS scores. Patients in the high-CSRGS group exhibited a worse prognosis, higher immune infiltration, and increased sensitivity to immune checkpoint blockade therapy. Furthermore, senescence-related pathways were significantly correlated with glycolysis, indicating upregulated glycolytic metabolism in senescent GBM cells. We identified TGFBI as a key regulator that played vital roles in both glycolysis and cellular senescence in GBM. TGFBI was overexpressed in GBM samples compared to normal brain tissues, and its knockdown via shRNA inhibited cellular senescence, glycolysis, and temozolomide resistance. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays confirmed that TGFBI is a direct STAT3 target and is required for the STAT3-induced promotion of cellular senescence, glycolysis, and drug resistance. The STAT3-TGFBI axis could be a potential target for senescence-targeted GBM therapy.

Since cancer is becoming a leading cause of death worldwide, efforts should be concentrated on understanding its underlying biological alterations that would be utilized in disease management, especially prevention strategies. Within this context, multiple bodies of evidence have highlighted leptin's practical and promising role, a peptide hormone extracted from adipose and fatty tissues with other adipokines, in promoting the proliferation, migration, and metastatic invasion of breast carcinoma cells. Excessive blood leptin levels and hyperleptinemia increase body fat content and stimulate appetite. Also, high leptin level is believed to be associated with several conditions, including overeating, emotional stress, inflammation, obesity, and gestational diabetes. It has been noted that when leptin has impaired signaling in CNS, causing the lack of its normal function in energy balance, it results in leptin resistance, leading to a rise in its concentration in peripheral tissues. Our research paper will shed highlighting on potentially targeting the leptin receptor and its cellular signaling in suppressing breast cancer progression.

Ubiquitin-specific peptidase 13 (USP13) has emerged as a key regulator of proteins critical to the hallmarks of cancer, playing an essential role in cellular regulation. This deubiquitinating enzyme, often overexpressed in malignancies, wields its molecular scissors precisely, snipping ubiquitin tags to rescue oncoproteins from degradation. Our review highlights the dual role of USP13 in cancer biology: while it predominantly fuels tumor growth and metastasis, USP13 occasionally functions as a tumor suppressor. USP13 is as a formidable factor in cancer therapy, fortifying tumors against an arsenal of treatments. It bolsters DNA repair mechanisms, ignites prosurvival autophagy, and even reprograms cell lineages to evade targeted therapies. However, USP13 is also a promising target in the treatment of cancer. We highlight burgeoning strategies to neutralize USP13, from small molecule inhibitors to innovative protein degraders, which may disarm cancer resistance mechanisms. We also offer suggestions for future USP13 research, emphasizing the need for structural insights and more potent inhibitors. This review highlights the critical role of USP13 in cancer and underscores its potential as a therapeutic target for advancing cancer treatment.

Obesity worsens cancer-specific survival and all-cause mortality for women diagnosed with breast cancer. Rich in adipose tissue, the breast exhibits increased adipocyte size in obesity, which correlates with poor prognosis. However, adipocyte size is highly heterogeneous as adipose tissue expands through both hyperplasia and hypertrophy; and adipocyte size can increase independently of weight gain. Despite these observations, the impact of adipocyte size on breast cancer cell behavior remains unclear due to insufficient approaches to isolate adipocytes based on size and maintain them in culture for mechanistic studies. Here, we develop strategies to culture size-sorted adipocytes from two mouse models of obesity and test their functional impact on tumor cell malignancy. We find that large adipocytes are transcriptionally distinct from small adipocytes and are enriched for gene sets related to adipose tissue dysfunction, including altered lipid processing. In coculture studies, large adipocytes promote lipid accumulation in breast cancer cells, and enhance their migration, proliferation, and aerobic metabolism in a manner dependent on fatty acid oxidation. These changes coincide with increased release of extracellular vesicles by large versus small adipocytes, which transfer lipid to recipient tumor cells. Moving forward, our findings suggest that adipocyte size could serve as a prognostic biomarker for women with breast cancer and help identify new therapeutic targets to advance clinical outcomes for these patients.

The acidic tumor microenvironment (TME) favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether adaptation to environmental acidosis (pH 6.5) selects for human pancreatic cancer stem cell (CSC) properties. RNA sequencing (RNA-seq) of acid-adapted (AA) Panc-1 cells revealed CSC pathway enrichment and upregulation of CSC markers. AA Panc-1 cells exhibited classical CSC characteristics including increased aldehyde dehydrogenase (ALDH) activity and β-catenin activity. Panc-1, PaTu8988s, and MiaPaCa-2 cells all exhibited increased pancreatosphere-forming efficiency after acid adaptation but differed in CSC marker expression and did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing revealed the acid adaptation-induced emergence of Panc-1 cell subpopulations with clear CSC characteristics. In orthotopic mouse tumors, AA Panc-1 cells exhibited enhanced aggressiveness, liver and lung metastasis, compared to controls. Collectively, our work suggests that acid adaptation enriches for pancreatic CSC phenotypes with unusual traits via several trajectories, providing new insight into how acidic microenvironments favor cancer aggressiveness.

Prostate cancer (PCa) is the most common urological malignancy and second only to lung cancer in incidence among men. Its prognosis varies widely due to its heterogeneity. Research indicates that fatty acid metabolism may play a role in tumor development.

The gene expression profiles of PCa cell lines (GSE6919) in GEO database were analyzed to identify differentially expressed genes and their significance in relation to progression-free interval. The R package was employed to assess overall survival significance and clinicopathological features. The study investigated the effects of gene mutations and methylation on PCa and their correlation with immune cell infiltration in the tumor microenvironment, utilizing cBioPortal and UALCAN resources. TIMER was used in the TCGA project to compare the expression of MECR in tumours and in adjacent normal tissue for different tumours or for specific tumour subtypes. Furthermore, we examined the impact of hub genes on PCa progression through RT qPCR, immunohistochemistry, and cellular assays.

The MECR gene, which plays a role in fatty acid metabolism, has been implicated in the development and progression of PCa. Its expression levels are significantly associated with clinical features, survival outcomes, and prognosis in PCa. Comprehensive analyses of MECR mutations and methylation levels further underscore its involvement in the progression of prostate cancer. Additionally, MECR is closely associated with the immune microenvironment and immune cell infiltration in PCa. Furthermore, the in vitro and in vivo data indicated that MECR plays a role in PCa proliferation, migration, and invasion.

MECR has significant potential for research and application in the assessment of PCa prognosis and the regulation of the immune microenvironment.

Triple-negative breast cancer (TNBC) presents an unmet medical challenge due to poor outcomes and limited treatment options. Metabolic signals are coupled to oncogenesis. Fatty acid oxidation (FAO) plays a crucial role in cancer initiation, progression, metastasis, and therapy resistance, but its precise functions and underlying molecular mechanisms in TNBC remain unclear. Here, we conducted a comprehensive study to investigate the biological roles and drug modulation of FAO in TNBC using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Genomics of Drug Sensitivity in Cancer (GDSC), and Connectivity Map (CMap) databases. We found that altered FAO activity was not related to patient age, clinical stage, tumor mutational burden, microsatellite instability, or homologous recombination deficiency. Nevertheless, upregulated FAO activity correlated with poor prognosis, increased stemness, accelerated cell cycle progression, altered mutation rates of several top 20 most frequently mutated genes, as well as higher activity of pathways involving oncogenic signaling, cellular metabolism, protein turnover, and so forth. Elevated FAO activity also appeared to foster an immunosuppressive microenvironment, influence microbial composition, and confer resistance to chemotherapies. What's more, we identified several compounds that may regulate FAO activity, including the HDAC inhibitor chidamide, which induced FAO activation in TNBC cells. Co-treatment with an FAO inhibitor etomoxir enhanced the combined effects of chidamide with established chemotherapy drugs, as well as their efficacy as single agents in TNBC cells. In conclusion, FAO likely exerts pleiotropic biological effects in TNBC and modulating FAO may offer a promising strategy to improve therapeutic outcomes in TNBC patients.

Myeloid-derived suppressor cells (MDSCs) in tumor microenvironment reduce the efficacy of immunotherapy. PKN2 plays a role in colon cancer, but its function in esophageal cancer (EC) remains unclear. This study investigated PKN2 expression in MDSCs derived from EC tissues and determined whether PKN2 regulates immunosuppressive activity of MDSCs by mediating fatty acid oxidation (FAO).

PKN2 expression was determined in GEO database, EC patients, and 4-NQO-induced EC mice, as well as in different types of immune cells. The effect of PKN2 on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was investigated by co-culture of PMN-MDSCs and CD4+/CD8+ T cells. The co-culture of patient-derived organoids and autologous immune cells was performed to observe the effect of PKN2 on the immunosuppressive function of PMN-MDSCs.

PKN2 is highly expressed in EC tumor tissues compared to normal tissues, especially in tumor-infiltrated PMN-MDSCs. Overexpressing PKN2 in PMN-MDSCs contributes to the immunosuppressive activity of PMN-MDSCs in vitro. PKN2-overexpressing PMN-MDSCs inhibited the killing ability of cytotoxic T lymphocytes and promoted EC organoid growth. PKN2 promotes FAO in PMN-MDSCs via CPT1B (a key enzyme of FAO). Mechanistically, PKN2 promotes CPT1B transcription by upregulating STAT3 phosphorylation.

PKN2 expression was increased in PMN-MDSCs derived from human and mouse EC tissues. PKN2 plays a role in enhancing the immunosuppressive activity of PMN-MDSCs by facilitating STAT3 phosphorylation and CPT1B transcription, which in turn leads to increased CPT1B-mediated FAO in PMN-MDSCs. Targeted inhibition of PKN2 is expected to improve immunotherapeutic efficacy in EC patients.

Over 60% of breast cancer cases are diagnosed with estrogen-receptor (ER) positive. Tamoxifen (TAM), a commonly employed medication for ER-positive breast cancer, often yields suboptimal therapeutic outcomes due to the emergence of TAM resistance, leading to the recurrence and a poor prognosis. The copper transporter, solute carrier family 31 member 1 (SLC31A1), has been associated with tumor aggressiveness and unfavorable outcomes in various types of tumors. In our current study, we found high expression of SLC31A1 that predicted poor survival in patients with breast cancer. Significantly, ER-positive breast cancer tissues in patients with recurrence post-TAM treatment exhibited considerably stronger SLC31A1 expression levels. In vitro experiments verified that TAM-resistant ER-positive breast cancer cell lines expressed notably higher SLC31A1 levels compared to the parental cell lines. Of great significance, SLC31A1 depletion notably rescued TAM sensitivity in chemoresistant ER-positive breast cancer cells, as demonstrated by the attenuated cell proliferative and invasive capabilities. Conversely, promoting SLC31A1 significantly facilitated the proliferation and invasion of wild-type breast cancer cells. Subsequently, we detected reduced copper levels in TAM-resistant breast cancer cells with SLC31A1 depletion. Mechanistically, we observed that in chemoresistant breast cancer cell lines, SLC31A1 knockdown resulted in a substantial decrease in the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of fatty acid oxidation (FAO). RNA-Seq analysis indicated that FAO might be implicated in SLC31A1-mediated breast cancer progression. CPT1A was also overexpressed in TAM-resistant breast cancer cells, accompanied by enhanced FAO rates and ATP levels. Suppressing CPT1A significantly enhanced the chemosensitivity of TAM-resistant breast cancer cells in response to TAM treatments. Intriguingly, copper exposure dose-dependently increased CPT1A expression in chemoresistant breast cancer cells, but this could be abolished upon SLC31A1 knockdown, along with enhanced apoptosis, which elucidated that copper uptake contributed to CPT1A expression. Furthermore, SLC31A1 overexpression significantly augmented CPT1A expression in parental breast cancer cells, accompanied by facilitated copper levels, FAO rates, and ATP levels, while being notably diminished upon CPT1A suppression. Finally, our in vivo studies confirmed that SLC31A1 deficiency re-sensitized TAM-resistant breast cancer cells to TAM treatment and abolished tumor growth. Collectively, all our studies demonstrated that SLC31A1/copper suppression could enhance TAM responses for chemoresistant ER-positive breast cancer cells through constraining the CPT1A-mediated FAO process.

Triple-negative breast cancer (TNBC) presents a formidable global health challenge, marked by its aggressive behavior and significant treatment resistance. This subtype, devoid of estrogen, progesterone, and HER2 receptors, largely relies on breast cancer stem cells (BCSCs) for its progression, metastasis, and recurrence. BCSCs, characterized by their self-renewal capacity and resistance to conventional therapies, exploit key surface markers and critical signaling pathways like Wnt, Hedgehog, Notch, TGF-β, PI3K/AKT/mTOR and Hippo-YAP/TAZ to thrive. Their adaptability is underscored by mechanisms including drug efflux and enhanced DNA repair, contributing to poor prognosis and high recurrence rates. The tumor microenvironment (TME) further facilitates BCSC survival through complex interactions with stromal and immune cells. Emerging therapeutic strategies targeting BCSCs - ranging from immunotherapy and nanoparticle-based drug delivery systems to gene-editing technologies - aim to disrupt these resistant cells. Additionally, innovative approaches focusing on exosome-mediated signaling and metabolic reprogramming show promise in overcoming chemoresistance. By elucidating the distinct characteristics of BCSCs and their role in TNBC, researchers are paving the way for novel treatments that may effectively eradicate these resilient cells, mitigate metastasis, and ultimately improve patient outcomes. This review highlights the urgent need for targeted strategies that address the unique biology of BCSCs in the pursuit of more effective therapeutic interventions for TNBC.

The highly nuanced transition from an inflammatory process to tumorigenesis is of great scientific interest. While it is well known that environmental stimuli can cause inflammation, less is known about the oncogenic modifications that chronic inflammation in the tissue microenvironment can bring about, as well as how these modifications can set off pro-tumorigenic processes. It is clear that no matter where the environmental factors come from, maintaining an inflammatory microenvironment encourages carcinogenesis. In addition to encouraging angiogenesis and metastatic processes, sustaining the survival and proliferation of malignant transformed cells, and possibly altering the efficacy of therapeutic agents, inflammation can negatively regulate the antitumoral adaptive and innate immune responses. Because chronic inflammation has multiple pathways involved in tumorigenesis and metastasis, it has gained recognition as a marker of cancer and a desirable target for cancer therapy. Recent advances in our knowledge of the molecular mechanisms that drive cancer's progression demonstrate that inflammation promotes tumorigenesis and metastasis while suppressing anti-tumor immunity. In many solid tumor types, including breast, lung, and liver cancer, inflammation stimulates the activation of oncogenes and impairs the body's defenses against the tumor. Additionally, it alters the microenvironment of the tumor. As a tactical approach to cancer treatment, these findings have underscored the importance of targeting inflammatory pathways. This review highlights the role of inflammation in cancer development and metastasis, focusing on its impact on tumor progression, immune suppression, and therapy resistance. It examines current anti-inflammatory strategies, including NSAIDs, cytokine modulators, and STAT3 inhibitors, while addressing their potential and limitations. The review emphasizes the need for further research to unravel the complex mechanisms linking inflammation to cancer progression and identify molecular targets for specific cancer subtypes.

Cell metabolism plays a crucial role in regulating the pluripotency of human embryonic stem cells (hESCs). Chlorogenic acid (CGA), an essential dietary polyphenol, exhibits diverse pharmacological effects on metabolism regulation. This study examines the effects of CGA on cell metabolism in hESCs using the H9 model. At a concentration of 100 µg/ml, CGA showed low toxicity and had no impact on the viability of H9 cells. Furthermore, it promotes NANOG expression. Importantly, CGA enhances Fatty acid β-oxidation (FAO), thus promoting the proliferation and lipid synthesis of H9 cells. Mechanistically, CGA-induced FAO generates acetyl-CoA, which enhances de novo lipid synthesis and hyperacetylates H3K27 at the promoter regions of associated genes, thereby enhancing their expression. This study highlights the potential beneficial effects of CGA on cell proliferation and provides opportunities for optimizing the in vitro culture of hESCs.

Cancer stem cells (CSCs) are central to tumor progression, metastasis, immune evasion, and therapeutic resistance. Characterized by remarkable self-renewal and adaptability, CSCs can transition dynamically between stem-like and differentiated states in response to external stimuli, a process termed "CSC plasticity." This adaptability underpins their resilience to therapies, including immune checkpoint inhibitors and adoptive cell therapies (ACT). Beyond intrinsic properties, CSCs reside in a specialized microenvironment-the CSC niche-which provides immune-privileged protection, sustains their stemness, and fosters immune suppression. This review highlights the critical role of CSCs and their niche in driving immunotherapy resistance, emphasizing the need for integrative approaches to overcome these challenges.

Gastric cancer (GC) remains one of the most common types of cancer, ranking fifth among cancer-related deaths worldwide. Chemotherapy is an effective treatment for advanced GC. However, the development of chemotherapy resistance, which involves the malfunction of several signaling pathways and is the consequence of numerous variables interacting, seriously affects patient treatment and leads to poor clinical outcomes. Therefore, in order to treat GC, it is imperative to find novel medications that will increase chemotherapy sensitivity and reverse chemotherapy resistance. Traditional Chinese medicine (TCM) has been extensively researched as an adjuvant medication in recent years. It has been shown to have anticancer benefits and to be crucial in enhancing chemotherapy sensitivity and reducing chemotherapy resistance. Given this, the mechanism of treatment resistance in GC is summed up in this work. The theoretical foundation for TCM as a sensitizer in adjuvant treatment of GC is established by introducing the primary signal pathways and possible targets implicated in improving chemotherapy sensitivity and reversing chemotherapy resistance of GC by TCM and active ingredients.

Breast cancer remains the most prevalent cancer among women globally, with significant links to obesity and lipid metabolism abnormalities. This review examines the role of lipid metabolism in breast cancer progression, highlighting its multifaceted contributions to tumor biology. We discuss key metabolic processes, including fatty acid metabolism, triglyceride metabolism, phospholipid metabolism, and cholesterol metabolism, detailing the reprogramming that occurs in these pathways within breast cancer cells. Alterations in lipid metabolism are emphasized for their roles in supporting energy production, membrane biogenesis, and tumor aggressiveness. Furthermore, we examine how lipid metabolism influences immune responses in the tumor microenvironment, affecting immune cell function and therapeutic efficacy. The potential of lipid metabolism as a target for novel therapeutic strategies is also addressed, with a focus on inhibitors of key metabolic enzymes. By integrating lipid metabolism with breast cancer research, this review underscores the importance of lipid metabolism in understanding breast cancer biology and developing treatment approaches aimed at improving patient outcomes.

Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC.

Hematopoietic stem cells (HSCs) maintain production of all functional blood cells and are located within the bone marrow. In pathological conditions, such as obesity or leukemia, changes in these cells contribute to disease pathophysiology. In this study, we examined the impact of metabolic modulation of stem and progenitor cells within the bone marrow during diet-induced obesity (DIO) and leukemia relapse. Avocatin B (Avo), an inhibitor of fatty acid oxidation (FAO), was provided in the diet and its impact on stem cells using two disease models was tested. In DIO, high fat diet(HFD)-induced alterations in HSC number and function were attenuated with Avo (HFD: 46.9% decrease compared to control; p < 0.001; whereas DIO + Avo: 58.8% recovery; p < 0.05). In leukemia relapse, dietary Avo delayed disease reoccurrence. Taken together, addition of Avo into the diet imparts protection in the bone marrow.

Homoharringtonine is a natural alkaloid with significant pharmacological potential that has demonstrated promising efficacy in the treatment of hematological malignancies in recent years. This article systematically reviews the pharmacological mechanisms of Homoharringtonine, focusing on its key roles in inducing apoptosis, inhibiting cell cycle progression, and reducing cell migration and invasion. Additionally, HHT exhibits multiple biological activities, including immunomodulation, antiviral effects, and anti-fibrotic properties, with recent studies also revealing its potential neuroprotective functions. In clinical trials, Homoharringtonine has demonstrated promising efficacy in the treatment of hematological malignancies, particularly in various types such as acute myeloid leukemia and chronic myeloid leukemia. Despite the significant antitumor effects observed in clinical applications, its low bioavailability and potential side effects remain major challenges that limit its widespread use. This article details the latest research advancements aimed at enhancing the bioavailability of Homoharringtonine, including various drug delivery systems such as nanoparticles and liposomes, as well as chemical modification strategies. These approaches not only improve HHT's bioavailability in vivo but also enhance its targeting ability while reducing toxicity to normal cells. Furthermore, the combination of HHT with other drugs presents broader prospects for clinical treatment. By exploring the diverse pharmacological activities of Homoharringtonine in depth, this article aims to provide a foundation for developing novel therapeutic approaches based on natural products, thereby advancing HHT's application research in cancer treatment and other fields.

Background: Breast cancer (BC) is a major health concern globally and the second leading cause of cancer-related mortality in women in Saudi Arabia. Although peoples' awareness of BC risk factors has been previously examined, studies on obesity-related BC awareness in the Qassim region are inconclusive. We aimed to evaluate knowledge and awareness of obesity-related BC risk among Saudi women in the Qassim region. Methods: This is a cross-sectional study with a stratified random sampling technique of 400 Saudi women randomly selected from the Qassim region through an online platform and community health centers. An online closed-ended pretested validated structured questionnaire was completed by the participants using a Google Forms link. The categorical variables were frequency and percentage. The chi-square test was used to study the relationship between the dependent and independent variables. Results: There is moderate to poor knowledge regarding breast cancer risk factors. The results showed poor knowledge about obesity after menopause as a risk factor for BC (49%). Over half of the participants (51.0%) did not consider obesity a BC risk factor. The need for self-examinations and mammogram screenings showed moderate (59.6%) and poor awareness levels (4.75%). Conclusions: The findings highlight a noticeable gap in knowledge and awareness about obesity-related BC risks, as well as a limited awareness of the need for breast self-examinations and mammogram screenings. These results underscore the urgent need for targeted awareness campaigns and educational programs in the Qassim region to address this critical health issue. Promoting breast self-examination practices, weight management, and regular mammogram screenings could significantly enhance early detection, improve prognosis, and reduce BC-related mortality among Saudi women in the Qassim region.

Breast cancer is the most commonly diagnosed type of cancer and the leading cause of cancer-related death in women worldwide. Highly targeted therapies have been developed for different subtypes of breast cancer, including hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, triple-negative breast cancer (TNBC) and metastatic breast cancer disease are primarily treated with chemotherapy, which improves disease-free and overall survival, but does not offer a curative solution for these aggressive forms of breast cancer. Moreover, the development of chemoresistance is a major cause of therapeutic failure in this neoplasia, leading to disease relapse and patient death. In addition, chemotherapy's adverse side effects may substantially worsen health-related quality of life. Therefore, to improve the outcome of patients with breast cancer who are undergoing chemotherapy, several therapeutic options are under investigation, including the combination of chemotherapeutic drugs with natural compounds. Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), including docosahexaenoic and eicosapentaenoic acids, have drawn attention for their antitumoral properties and their preventive activities against chemotherapy-induced toxicities in breast cancer. A literature review was conducted on PubMed using keywords related to breast cancer, omega-3, chemoresistance, and chemotherapy. This review aims to provide an overview of the molecular mechanisms driving breast cancer chemoresistance, focusing on the role of ω-3 PUFAs in these recognized cellular paths and presenting current findings on the effects of ω-3 PUFAs combined with chemotherapeutic drugs in breast cancer management.

Lipoapoptosis in Proximal tubular epithelial cells (PTCs) are substantial in the etiology of diabetic kidney disease (DKD), yet the underlying mechanisms warrant further investigation. Acyl-CoA synthetase long-chain family member 5 (ACSL5) facilitates the formation of acyl-CoA, however, the precise role of ACSL5 in lipoapoptosis of PTCs in DKD remains inconclusive.

Transcriptomic data analysis identified the hub gene Acsl5 associated with lipid metabolism in DKD. The expression of ACSL5 was examined in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice and high glucose/palmitic acid (HGPA)-induced mouse proximal tubular epithelial cell (BUMPT). Oil Red O staining, free fatty acids (FFA) ELISA assay, Western Blot, and morphological changes were employed to assess lipid deposition and lipoapoptosis. Furthermore, knockdown and overexpression of ACSL5 were conducted in BUMPT cells, followed by morphological assessment, Oil Red O staining, FFA ELISA assay and Western Blot analysis. Using the ChEA3 database, we predicted that STAT3 may transcriptionally regulate ACSL5. Subsequently, we knocked down STAT3 and evaluated Acsl5 expression via RT-qPCR. Additionally, we investigated whether STAT3 modulates the impact of ACSL5 on lipoapoptosis through Western Blot analysis.

We demonstrated, for the first time, a notable upregulation of ACSL5 expression in PTCs in HFD/STZ-induced diabetic mice, accompanied by increased the expression of FATP2, lipid accumulation and heightened lipoapoptosis. In HGPA-treated BUMPT cells, ACSL5 knockdown reduced the expression of FATP2, lipid deposition and lipoapoptosis, whereas its overexpression elevated the expression of FATP2 and exacerbated these effects. These findings strongly suggest that ACSL5 may exacerbate lipoapoptosis in PTCs within a diabetic milieu. From a molecular mechanism perspective, ACSL5 expression decreased after Stat3 knockdown. Concurrent knockdown of Stat3 and overexpression of Acsl5 led to a mitigation of lipoapoptosis compared to sole Acsl5 overexpression. Furthermore, STAT3 promotes the activation of ACSL5 promoter under HGPA conditions.

In summary, our research identified ACSL5 as an important contributor exacerbating lipoapoptosis in the renal proximal tubules within diabetic environments. In addition, we found that ACSL5 is transcriptionally regulated by STAT3.

Lipids are the key component of all membranes composed of a variety of molecules that transduce intracellular signaling and provide energy to the cells in the absence of nutrients. Alteration in lipid metabolism is a major factor for cancer heterogeneity and a newly identified cancer hallmark. Reprogramming of lipid metabolism affects the diverse cancer phenotypes, especially epithelial-mesenchymal transition (EMT). EMT activation is considered to be an essential step for tumor metastasis, which exhibits a crucial role in the biological processes including development, wound healing, and stem cell maintenance, and has been widely reported to contribute pathologically to cancer progression. Altered lipid metabolism triggers EMT and activates multiple EMT-associated oncogenic pathways. Although the role of lipid metabolism-induced EMT in tumorigenesis is an attractive field of research, there are still significant gaps in understanding the underlying mechanisms and the precise contributions of this interplay. Further study is needed to clarify the specific molecular mechanisms driving the crosstalk between lipid metabolism and EMT, as well as to determine the potential therapeutic implications. The increased dependency of tumor cells on lipid metabolism represents a novel therapeutic target, and targeting altered lipid metabolism holds promise as a strategy to suppress EMT and ultimately inhibit metastasis.

Lipid droplets are fat storage organelles composed of a protein envelope and lipid-rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all-trans-retinal to all-trans-retinol, is upregulated in the MITFLO/undifferentiated/neural crest-like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid-mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.

Triple-negative breast cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming especially fatty acid oxidation (FAO) has emerged as a major driver of breast cancer metastasis. Analyzing the expression of major FAO regulatory genes in breast cancer, we found selective overexpression of acyl-CoA synthetase 4 (ACSL4) in TNBC, which is primarily attributed to the absence of progesterone receptor. Loss of ACSL4 function, by genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity positively influences the gene expression related to TNBC migration and invasion. Mechanistically, ACSL4 modulates FAO and intracellular acetyl-CoA levels, leading to hyperacetylation of particularly H3K9ac and H3K27ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lung. Further, human TNBC metastasis exhibits positive correlation among ACSL4, H3K9ac, H3K27ac, and SNAIL expression. Altogether, our findings provide molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis, and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.