The mevalonate (MVA) pathway plays a critical role in cholesterol biosynthesis, protein prenylation, and metabolic reprogramming, all of which contribute to cancer progression and therapy resistance. Targeting the MVA pathway with statins and other inhibitors has shown promise in preclinical studies; however, clinical outcomes remain controversial, raising concerns about translating these findings into effective treatments. Additionally, the interaction between the MVA pathway and radiation therapy (RT) is not yet fully understood, as RT upregulates the pathway, which can enhance tumor cell survival. This review summarizes the current literature on MVA pathway inhibition in cancer therapy, focusing on its potential to enhance the efficacy of RT. A better understanding of the pathway's role in radiation responses will be essential to translate combination therapies that target this pathway.

Metabolic reprogramming is a hallmark of malignant transformation. While initial studies in the field of cancer metabolism focused on central carbon metabolism, the field has expanded to metabolism beyond glucose and glutamine and uncovered the important role of amino acids in tumorigenesis and tumor immunity as energy sources, signaling molecules, and precursors for (epi)genetic modification. As a result of the development and application of new technologies, a multifaceted picture has emerged, showing that context-dependent heterogeneity in amino acid metabolism exists between tumors and even within distinct regions of solid tumors. Understanding the complexity and flexibility of amino acid metabolism in cancer is critical because it can influence therapeutic responses and predict clinical outcomes. This overview discusses the current findings on the heterogeneity in amino acid metabolism in cancer and how understanding the metabolic diversity of amino acids can be translated into more clinically relevant therapeutic interventions.

Increased expression of glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of cancer, including breast, lung, and pancreatic cancer. G9a histone methyltransferase inhibitors may have anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a histone methyltransferase inhibitor, can inhibit glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.

The effects of BIX on mitochondrial metabolism in PDAC cells were evaluated by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.

BIX significantly inhibited the growth of PDAC cells, both in vitro and in vivo, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP+/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-l-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a histone methyltransferase. One Jumonji-domain histone demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.

Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.

Pancreatic cancer (PC) is one of the most malignant tumors, with a 5‑year survival rate <10%. Chemosynthetic drugs are widely used in the treatment of PC; however, their toxicity and side effects often reduce the quality of life for patients. MTT and colony formation assay were performed to detect cell growth and viability in PC cells. Levels of ROS in whole cell and mitochondria were analyzed through flow cytometry. ATP production was evaluated using an ATP Assay Kit. Cellular bioenergetics were analyzed with a Seahorse XFe96 Analyzer, and changes in target molecules were monitored by western blotting. The present study reports that fucoxanthin (FX), a carotenoid derived from aquatic brown seaweed, significantly inhibits PC by inhibiting cell proliferation and inducing cell death via the non‑classical pathway. FX switches mitochondrial respiration to aerobic glycolysis in PC cells. Furthermore, FX decreases whole‑cell ATP levels, which indicates that promotion of glycolysis does not compensate for FX‑induced ATP depletion in mitochondria. Moreover, FX decreased the reduced glutathione/oxidized glutathione ratio observed under glucose‑limited conditions. These alterations caused by FX may decrease metabolic flexibility, indicating higher sensitivity to glucose‑limited (GL) conditions. FX increased the cytotoxicity of cisplatin (DDP) and the expression of solute carrier family 31 member 1 (SLC31A1) in PC cells. Furthermore, the knockdown of SLC31A1 can attenuate cytotoxicity caused by the combination of FX and DDP. It was inferred that FX increased the sensitivity of PC cells to DDP), potentially by upregulating SLC31A1 expression. In conclusion, FX exhibited potent antitumor effects by reprogramming energy metabolism and inducing a distinct form of regulated cell death. Therefore, combining FX with GL treatment or DDP presents a promising therapeutic strategy for PC.

Fifteen new cadinane sesquiterpenoids, amorphaenes A-O (1-15), along with one known compound, were isolated from an endophytic fungus Penicillium sp. HZ-5 collected from Hypericum wilsonii N. Robson. Notably, compound 7 was the first example of 11-nor cadinane sesquiterpenoid via the oxidative cleavage between C-11 and C-13. Their structures were elucidated by extensive spectroscopic analysis, singlecrystal X-ray diffraction and ECD calculation and comparison. Significantly, compounds 1, 5, 8, 13 and 16 exhibited glutamic oxaloacetate transaminase 1 (GOT1) inhibitory effects, with IC50 values ranging from 20.0 ± 2.1 to 26.2 ± 2.7 μM and also showed potential cytotoxicity on pancreatic ductal adenocarcinoma (PDAC) cells, with IC50 values ranging from 13.1 ± 1.5 to 28.6 ± 2.9 μM.

Current evidence indicates that circRNAs are involved in the development of multiple malignancies including hepatocellular carcinoma (HCC). However, the specific functions of circRNAs in HCC metabolism and progression and their underlying regulatory mechanisms remain unclear. We have identified a novel circRNA circMFN2, by bioinformatics analysis of circRNA microarray data from the GEO database. The levels of circMFN2 were assessed in HCC cell lines and tissues, and its clinical relevance was assessed. The effect of circMFN2 on HCC cells was evaluated in vitro and in vivo. The effect of ELK1 on glutaminolysis and HCC progression was also explored. Patients with HCC and high circMFN2 expression exhibited worse survival outcomes. Functionally, downregulation of circMFN2 repressed the proliferation, invasion, and migration of HCC cells in vitro, whereas ectopic expression of circMFN2 had the opposite effects. The effects of tumor enhancement by circMFN2 on HCC were confirmed by in vivo experiments. Mechanistically, circMFN2 acted as a sponge for miR-361-3p, leading to the upregulation of its target ELK1, whereas ELK1 was enriched in the MFN2 promoter to enhance the transcription and expression of MFN2, indirectly leading to the upregulation of circMFN2. Additionally, we found that circMFN2 promotes glutaminolysis in HCC by increasing ELK1 phosphorylation. We concluded that circMFN2 facilitates HCC progression via a circMFN2/miR-361-3p/ELK1 feedback loop, which promotes glutaminolysis mediated by the upregulation of phosphorylated ELK1. Therefore, circMFN2 not only serves as a potential prognostic indicator, but it could also serve as a therapeutic target for HCC. Further studies are warranted.

Both obesity and metabolic disorders are global medical problems. Driven by prolonged inflammation, obesity increases the risk of developing metabolic syndromes such as fatty liver, diabetes, cardiovascular diseases and cancers. The fat mass and obesity-associated protein (FTO) is an m6A demethylase, elevated activity of which is known to promote the pathogenesis of many metabolic disorders, leading to the establishment of various FTO inhibitors. By combing through intrinsic connections among obesity and the four primary metabolic problems, we attribute their shared pathological cause to prolonged inflammation. By reviewing the roles of FTO in promoting these disorders and the current status of existing FTO inhibitors in treating these syndromes, we underpinned the paramount potential of resolving these clinical issues by targeting FTO and the urgent need of establishing novel FTO inhibitors with maximized efficacy and minimized side effect. Cold atmospheric plasma (CAP) is the fourth state of matter with demonstrated efficacy in treating various diseases associated with chronic inflammation. By introducing the medical characteristics of CAP, we proposed it as a possible solution to unresolved issues of current FTO inhibitors given its anti-inflammation feature and demonstrated clinical safety. We also emphasized the need of intensive investigations in exploring the feasibility of using CAP in treating obesity and associated metabolic syndromes that might function through targeting FTO.

Pancreatic cancer is a highly malignant digestive tumor. Glutamine metabolism is one of the important sources of tumors. N6-methyladenosine (m6A) modification plays a key role in regulating tumor metabolism and holds promise as a therapeutic target in various cancers, including pancreatic cancer. Disrupting m6A regulation of glutamine metabolism could impair tumor growth, offering potential new therapeutic strategies. However, the functional role of m6A modifications in pancreatic cancer, especially in glutamine metabolism, remains poorly understood.

The Cancer Genome Atlas (TCGA) dataset and GEPIA bioinformatics tool were used to identify the relationship between m6A related proteins and the glutamine metabolism-associated genes, respectively. The biological effects of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were investigated using in vitro and in vivo models. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-PCR and RNA immunoprecipitation (RIP) were used to identify solute carrier family 1 member 5 (SLC1A5) as a direct target of IGF2BP2.

We found that IGF2BP2 expression and SLC1A5 were significantly correlated and both highly expressed in pancreatic cancer could predict poor prognosis in patients with pancreatic cancer. Functionally, silencing IGF2BP2 suppressed tumor growth and also inhibited glutamine uptake by tumor cells. Mechanistically, IGF2BP2 induced the m6A-SLC1A5-mTORC1 axis, facilitating the uptake of glutamine by pancreatic cancer cells and accelerate the progress of pancreatic cancer. Furthermore, silencing IGF2BP2 can enhance the sensitivity of pancreatic cancer to radiotherapy and chemotherapy.

Our findings suggest that IGF2BP2 promotes pancreatic cancer by activating the m6A-SLC1A5 -mTORC1 axis. Targeting the m6A machinery, particularly IGF2BP2, offers a novel therapeutic avenue for pancreatic cancer treatment. By disrupting the regulation of glutamine metabolism, we provide new insights into how m6A-based therapies could enhance the efficacy of current treatments and offer hope for improving patient outcomes in this difficult-to-treat cancer.

Patients with advanced cancer frequently endure severe pain, which substantially diminishes their quality of life and can adversely impact survival. Analgesia, a critical modality for alleviating such pain, is now under scrutiny for its potential role in cancer progression, a relationship whose underlying mechanisms remain obscure. Emerging evidence suggests that lactate, once considered a metabolic byproduct, actively participates in the malignant progression of cancer by modulating both metabolic and immunological pathways within the tumor microenvironment. Furthermore, lactate is implicated in the modulation of cancer-related pain, exerting effects through direct and indirect mechanisms. This review synthesizes current understanding of lactate's production, transport, and functional roles in tumor cells, encompassing the regulation of tumor metabolism, immunity, and progression. Additionally, we dissect the complex, bidirectional relationship between lactate and pain, and assess the impact of anesthetics on pain relief, lactate homeostasis, and tumorigenesis.

Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.

Disrupted pH homeostasis can precipitate cell death and represents a viable therapeutic target in oncological interventions. Here, we utilize mass spectrometry-based drug analysis, transcriptomic screens, and lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent cell death. We reveal CYP51A1, a gene involved in cholesterol synthesis, as a key suppressor of alkalization-induced cell death in pancreatic cancer cells. Inducing intracellular alkalization by the small molecule JTC801 leads to a decrease in endoplasmic reticulum cholesterol levels, subsequently activating SREBF2, a transcription factor responsible for controlling the expression of genes involved in cholesterol biosynthesis. Specifically, SREBF2-driven upregulation of CYP51A1 prevents cholesterol accumulation within lysosomes, leading to TMEM175-dependent lysosomal proton efflux, ultimately resulting in the inhibition of cell death. In animal models, including xenografts, syngeneic orthotopic, and patient-derived models, the genetic or pharmacological inhibition of CYP51A1 enhances the effectiveness of JTC801 in suppressing pancreatic tumors. These findings demonstrate a role of the CYP51A1-dependent lysosomal pathway in inhibiting alkalization-induced cell death and highlight its potential as a targetable vulnerability in pancreatic cancer.

Cleft palate (CP) is a common congenital craniofacial malformation, which is caused by a combination of genetic and environmental factors. However, its underlying mechanism has not been elucidated. Sirtuin6 (SIRT6) mutation has been associated with craniofacial anomalies in humans. This study further defined the role of Sirt6 in palatogenesis by investigating the specific inactivation of Sirt6 in Wnt1-expressing cell lineages. Here, we demonstrated that Sirt6 conditioned knockout (Sirt6 cKO) could inhibit the osteogenesis of the palate which facilitated the occurrence of CP. Specifically, Sirt6 deficiency promoted the expression of glutamine oxaloacetic transaminase 1 (Got1) and glycolysis through deacetylation inhibition, which increased the proliferation of mouse embryonic palatal mesenchyme (MEPM) cells through the GOT1-lactate dehydrogenase A (LDHA)-transforming growth factor beta receptor 1 (TGFBR1) pathway in the early stage and inhibited the osteogenic differentiation of MEPM cells through the GOT1-LDHA-bone morphogenetic protein 2 (BMP2) pathway in the late stage. Notably, if there was a disturbance of the environment, such as retinoic acid (RA), the occurrence of CP increased. Also, the enhanced acetylation of histone 3 lysine 9 (H3K9) in Got1 induced by Sirt6 deficiency was mediated by the acetylase tat-interacting protein 60 (TIP60) rather than acetyltransferase p300 (P300). Additionally, inhibition of Got1 partially saved the promoting effect of Sirt6 cKO on the CP. Our study reveals the role of Sirt6 in facilitating CP, with Got1 as the primary driver.

Pancreatic ductal adenocarcinoma (PDAC) poses significant therapeutic challenges due to excessive hyaluronic acid (HA) accumulation, which impedes drug delivery. Here, we present a targeted approach to reduce HA production by specifically silencing glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), a key enzyme of the hexosamine biosynthesis pathway (HBP) in pancreatic cancer cells. An engineered liposomal system for siGFAT1 delivery, PMLip@siGFAT1, characterized by macrophage membrane camouflage, LFC131 peptide-mediated targeting, and calcium phosphate (CaP) as the core, was designed to ensure prolonged circulation, enhanced inflamed vascular endothelial penetration, and subsequent effective tumor cell uptake and endosomal escape. Consequently, PMLip@siGFAT1 markedly downregulated the HA level in the PDAC microenvironment, decompressing the tumor vasculature and weakening the stromal barrier, which in turn improved the permeability of chemotherapeutics. In combination with Doxil, PMLip@siGFAT1 demonstrated potent antitumor efficacy with minimal systemic toxicity. Importantly, unlike PEGPH20 (hyaluronidase), PMLip@siGFAT1 reduced tumor invasiveness, while preserving skeletal muscle integrity. These findings highlight that PMLip@siGFAT1 holds great potential to revitalize HA downregulation strategies in pancreatic cancer for enhanced drug delivery and efficacy.

Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism. Indeed, TFEB knockdown (KD) inhibited mammosphere formation in vitro and tumor initiation/growth in vivo. These phenotypic effects were accompanied by a decline in CD44high/CD24low cells. Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) induced TFEB nuclear translocation, indicative of TFEB transcriptional activity. TFEB KD blunted, whereas TFEB (S142A) augmented 2-DG-driven unfolded protein response (UPR) mediators, notably BiP/HSPA5 and CHOP. Like TFEB KD, silencing BiP/HSPA5 inhibited CSC self-renewal, suggesting that TFEB augments UPR-related survival. Further studies showed that TFEB KD attenuated 2-DG-directed autophagy, suggesting a mechanism whereby TFEB protects CSCs against 2-DG-induced stress. Our data indicate that TFEB modulates CSC metabolic stress response via autophagy and UPR. These findings reveal the novel role of TFEB in regulating CSCs during metabolic stress in triple-negative breast cancer.

Glutamine metabolism supports the development and progression of many cancers and is considered a therapeutic target. Attempts to inhibit glutamine metabolism have resulted in limited success and have not translated into clinical benefit. The outcomes of these clinical studies, along with preclinical investigations, suggest that cellular stress responses to glutamine deprivation or targeting may be modeled as a biphasic hormetic response. By recognizing the multifaceted aspects of glutamine metabolism inhibition within a more comprehensive biological framework, the adoption of this model may guide future fundamental and translational studies. To achieve clinical efficacy, we posit that as a field we will need to anticipate the hormetic effects of glutamine stress and consider how best to co-target cancer cell adaptive mechanisms.

Photoreceptor loss results in vision loss in many blinding diseases, and metabolic dysfunction underlies photoreceptor degeneration. So, exploiting photoreceptor metabolism is an attractive strategy to prevent vision loss. Yet, the metabolic pathways that maintain photoreceptor health remain largely unknown. Here, we investigated the dependence of photoreceptors on glutamine (Gln) catabolism. Gln is converted to glutamate via glutaminase (GLS), so mice lacking GLS in rod photoreceptors were generated to inhibit Gln catabolism. Loss of GLS produced rapid rod photoreceptor degeneration. In vivo metabolomic methodologies and metabolic supplementation identified Gln catabolism as critical for glutamate and aspartate biosynthesis. Concordant with this amino acid deprivation, the integrated stress response (ISR) was activated with protein synthesis attenuation, and inhibiting the ISR delayed photoreceptor loss. Furthermore, supplementing asparagine, which is synthesized from aspartate, delayed photoreceptor degeneration. Hence, Gln catabolism is integral to photoreceptor health, and these data reveal a novel metabolic axis in these metabolically-demanding neurons.

Gliomas, the most prevalent type of central nervous system tumors, currently lack effective therapeutic options. Lipolysis-stimulated lipoprotein receptors (LSR) have been implicated in tumor development and progression. This study aims to investigate the influence of LSR on gliomas and elucidate the underlying mechanisms.

We analyze LSR expression in gliomas and its association with patient prognosis using bioinformatics tools. Western blotting and immunohistochemistry revealed differential expression of LSR across different grades of glioma. The effects of LSR on glioma cell proliferation and invasion are evaluated through a series of cellular assays. Subcutaneous xenografts in nude mice are utilized to assess the impact of LSR on gliomas in vivo. Additionally, western blotting is employed to detect changes in protein levels related to the FOXO3a signaling pathway following LSR overexpression.

LSR expression is higher in tissues from low-grade gliomas compared to those from glioblastomas. Patients with low LSR expression exhibit poorer prognoses. Overexpression of LSR inhibit glioma cell proliferation and invasion. The protein levels of PCNA, Cyclin D1, MMP2, and MMP9 are significantly decreased in the OE-LSR group. Tumor volume is reduced in nude mice injected subcutaneously with LSR-overexpressing glioma cells. Overexpression of LSR increases nuclear FOXO3a level while reduces p-FOXO3a and p-14-3-3 levels. Knockdown of FOXO3a reverse the inhibitory effects of LSR overexpression on glioma cell proliferation and invasion.

Low LSR expression is associated with adverse prognosis in glioma patients. By modulating FOXO3a, LSR overexpression suppresses glioma cell proliferation and invasion.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown a dismal survival prognosis, resulting in less than a year of life in the metastatic setting. Methods: The pressing need to find better therapeutic methods brought about the discovery of new targeted therapies against the infamous KRAS mutations, the major oncological drivers of PDAC. Results: The most common KRAS mutation is KRASG12D, which causes a conformational change in the protein that constitutively activates downstream signaling pathways driving cancer hallmarks. Novel anti-KRASG12D therapies have been developed for solid-organ tumors, including small compounds, pan-RAS inhibitors, protease inhibitors, chimeric T cell receptors, and therapeutic vaccines. Conclusions: This comprehensive review summarizes current knowledge on the biology of KRAS-driven PDAC, the latest therapeutic options that have been experimentally validated, and developments in ongoing clinical trials.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC's response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy.

Serine metabolism provides important metabolic intermediates that support the rapid proliferation of tumor cells. However, the role of serine metabolism in esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remains unclear. Here, we show that serine starvation predominantly inhibits ESCC cell proliferation by suppressing purine nucleotides and NADPH synthesis. Mechanistically, serine depletion led to the accumulation of aminoimidazole carboxamide ribonucleoside (AICAR), an intermediate metabolite of de novo purine synthesis, and AMP/ATP ratio. These increases activated 5'-AMP-activated kinase (AMPK), which subsequently inhibited the mTORC1 pathway by phosphorylating Raptor at Ser792. Moreover, serine depletion decreased NADPH level followed by elevated reactive oxygen species (ROS) production and DNA damage, which induced p53-p21 mediated G1 phase cell cycle arrest. Conversely, serine starvation activated transcription factor 4 (ATF4)-mediated robust expression of phosphoserine aminotransferase 1 (PSAT1) which in turn promoted compensatory endogenous serine synthesis, thus maintaining ESCC cell survival under serine-limited conditions. Accordingly, serine deprivation combined with PSAT1 inhibition significantly suppressed ESCC tumor growth both in vitro and in vivo. Taken together, our findings demonstrate that serine starvation suppresses the proliferation of ESCC cells by disturbing the synthesis of purine nucleotides and NADPH, and the combination of serine deprivation and PSAT1 inhibition significantly impairs ESCC tumor growth. Our study provides a theoretical basis for targeting serine metabolism as a potential therapeutic strategy for ESCC.

Elevated PD-L1 expression in tumor cells facilitates immune evasion. However, the mechanism via which PD-L1 expression is regulated in pancreatic ductal adenocarcinoma (PDAC) cells remains inadequately elucidated.

Immunoprecipitation, pull-down assays, and mass spectrometry were used to identify glutamine synthase 2 (GLS2) and yes1 associated transcriptional regulator (YAP1) binding proteins and modification sites. Immunoblotting, immunofluorescence, chromatin immunoprecipitation, and luciferase reporter assays were used to analyze YAP1 activation. Protein expression levels were assessed using immunoblotting, immunoprecipitation, immunofluorescence, and immunohistochemistry. RNA expression levels were analyzed using RT-qPCR.

Hypoxia-induced GCN5-mediated acetylation of GLS2 at K151, which enhanced GLS2 interaction with YAP1. Subsequently, tubulin tyrosine ligase-like 1 mediated YAP1 glutamylation at E100 and promoted its nuclear translocation and the activation-dependent transcriptional up-regulation of PD-L1 expression. The expression of GLS2-K151R or YAP1-E100A mutants in PDAC cells blocked hypoxia-induced PD-L1 expression and enhanced CD4+ and CD8+ T-cell activation and tumor infiltration, thereby suppressing PDAC tumor growth. Simultaneous administration of MB-3, a GCN5 inhibitor, and an anti-PD-1 antibody abolished tumor immune evasion, boosting the anti-tumor efficacy of immune checkpoint blockade. Furthermore, GLS2-K151 acetylation and YAP1 E100 glutamylation levels correlated positively with PD-L1 expression and poor prognosis in PDAC patients.

The present study revealed a novel mechanism by which hypoxia up-regulates PD-L1 expression and highlighted the involvement of GLS2 in noncanonical metabolic pathways involved in tumor immune evasion, with implications for PDAC treatment.

Higher and richer nutrient requirements are typical features that distinguish tumor cells from AU: cells, ensuring adequate substrates and energy sources for tumor cell proliferation and migration. Therefore, nutrient deprivation strategies based on targeted technologies can induce impaired cell viability in tumor cells, which are more sensitive than normal cells. In this review, nutrients that are required by tumor cells and related metabolic pathways are introduced, and anti-tumor strategies developed to target nutrient deprivation are described. In addition to tumor cells, the nutritional and metabolic characteristics of other cells in the tumor microenvironment (including macrophages, neutrophils, natural killer cells, T cells, and cancer-associated fibroblasts) and related new anti-tumor strategies are also summarized. In conclusion, recent advances in anti-tumor strategies targeting nutrient blockade are reviewed, and the challenges and prospects of these anti-tumor strategies are discussed, which are of theoretical significance for optimizing the clinical application of tumor nutrition deprivation strategies.

Ferroptosis is a regulated cell death mechanism distinct from apoptosis, autophagy, and necroptosis, marked by iron accumulation and lipid peroxidation. Since its identification in 2012, it has developed into a potential therapeutic target, especially concerning GI disorders like PC, HCC, GC, and CRC. This interest arises from the distinctive role of ferroptosis in the progression of diseases, presenting a new avenue for treatment where existing therapies fall short. Recent studies emphasize the promise of focusing on ferroptosis to fight GI cancers, showcasing its unique pathophysiological mechanisms compared to other types of cell death. By comprehending how ferroptosis aids in the onset and advancement of GI diseases, scientists aim to discover novel drug targets and treatment approaches. Investigating ferroptosis in gastrointestinal disorders reveals exciting possibilities for novel therapies, potentially revolutionizing cancer treatment and providing renewed hope for individuals affected by these tumors.

Malic enzyme 1 (ME1) plays a key role in promoting malignant phenotypes in various types of cancer. ME1 promotes epithelial-mesenchymal transition (EMT) and enhances stemness via glutaminolysis, energy metabolism reprogramming from oxidative phosphorylation to glycolysis. As a result, ME1 promotes the malignant phenotypes of cancer cells and poor patient prognosis. In particular, ME1 expression is promoted in hypoxic environments associated with hypoxia-inducible factor (HIF1) α. ME1 is overexpressed in budding cells at the cancer invasive front, promoting cancer invasion and metastasis. ME1 also generates nicotinamide adenine dinucleotide (NADPH), which, together with glucose-6-phosphate dehydrogenase (G6PD) and isocitrate dehydrogenase (IDH1), expands the NADPH pool, maintaining the redox balance in cancer cells, suppressing cell death by neutralizing mitochondrial reactive oxygen species (ROS), and promoting stemness. This review summarizes the latest research insights into the mechanisms by which ME1 contributes to cancer progression. Because ME1 is involved in various aspects of cancer and promotes many of its malignant phenotypes, it is expected that ME1 will become a novel drug target in the near future.

Esophageal cancer (EC) is the seventh-most prevalent cancer worldwide and is a significant contributor to cancer-related mortality. Metabolic reprogramming in tumors frequently coincides with aberrant immune function alterations, and extensive research has demonstrated that perturbations in energy metabolism within the tumor microenvironment influence the occurrence and progression of esophageal cancer. Current treatment modalities for esophageal cancer primarily include encompass chemotherapy and a limited array of targeted therapies, which are hampered by toxicity and drug resistance issues. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, has exhibited promising results; however, a substantial proportion of patients remain unresponsive. The optimization of these immunotherapies requires further investigation. Mounting evidence underscores the importance of modulating metabolic traits within the tumor microenvironment (TME) to augment anti-tumor immunotherapy.

We selected relevant studies on the metabolism of the esophageal cancer tumor microenvironment and immune cells based on our searches of MEDLINE and PubMed, focusing on screening experimental articles and reviews related to glucose metabolism, amino acid metabolism, and lipid metabolism, as well their interactions with tumor cells and immune cells, published within the last five years. We analyzed and discussed these studies, while also expressing our own insights and opinions.

A total of 137 articles were included in the review: 21 articles focused on the tumor microenvironment of esophageal cancer, 33 delved into research related to glucose metabolism and tumor immunology, 30 introduced amino acid metabolism and immune responses, and 17 focused on the relationship between lipid metabolism in the tumor microenvironment and both tumor cells and immune cells.

This article delves into metabolic reprogramming and immune alterations within the TME of EC, systematically synthesizes the metabolic characteristics of the TME, dissects the interactions between tumor and immune cells, and consolidates and harnesses pertinent immunotherapy targets, with the goal of enhancing anti-tumor immunotherapy for esophageal cancer and thereby offering insights into the development of novel therapeutic strategies.

Metabolic reprogramming is increasingly recognized as a crucial factor influencing the development, progression, and prognosis of pancreatic ductal adenocarcinoma (PDAC). Despite this, the potential association of specific metabolic characteristics and PDAC remains ambiguous due to the variability introduced by individual patient differences. In this study, we aimed to find out metabolic pathways that may be associated with the overall survival (OS) of PDAC patients.

We utilized Mendelian randomization (MR) to assess the associations between 1400 metabolites and metabolite ratios and PDAC. We performed functional annotation and pathway enrichment analysis on both significant metabolites and the shared proteins corresponding to the significant metabolite ratios. Additionally, we analyzed peripheral blood metabolites from 32 PDAC patients to correlate metabolites with clinicopathological features and OS. Functional enrichment analysis was also conducted on the significant metabolites.

Our MR analysis revealed 55 metabolites/metabolite ratios associated with PDAC. Among the top 20 enriched metabolic pathways involving proteins related to significant metabolite ratios, seven were associated with amino acid metabolism, three with carbohydrate metabolism, and two with lipid metabolism. Serum metabolomics of PDAC patients highlighted significant upregulation in pathways related to primary bile acid biosynthesis, as well as taurine and hypotaurine metabolism, which correlated negatively with OS. Conversely, pathways involved in arginine biosynthesis, arginine and proline metabolism, and aminoacyl-tRNA biosynthesis were notably downregulated and positively associated with OS. Both upregulated and downregulated differential metabolites were notably enriched in the pyrimidine metabolism pathway, which was linked to poorer OS. These associations were corroborated by MR analysis.

The study provides valuable insights into the metabolic characteristics associated with PDAC, offering a reference point for improving diagnosis and treatment for PDAC.

The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the role of metabolic alterations in KRAS-driven cancers, providing a scientific rationale for targeting metabolism in cancer treatment. The development of KRAS-specific inhibitors has also garnered considerable attention, partly due to the challenge of acquired treatment resistance. Here, we review the metabolic reprogramming of glucose, glutamine, and lipids regulated by oncogenic KRAS, with an emphasis on recent insights into the relationship between changes in metabolic mechanisms driven by KRAS mutant and related advances in targeted therapy. We also focus on advances in KRAS inhibitor discovery and related treatment strategies in colorectal, pancreatic, and non-small cell lung cancer, including current clinical trials. Therefore, this review provides an overview of the current understanding of metabolic mechanisms associated with KRAS mutation and related therapeutic strategies, aiming to facilitate the understanding of current challenges in KRAS-driven cancer and to support the investigation of therapeutic strategies.

The importance of redox systems as fundamental elements in biology is now widely recognized across diverse fields, from ecology to cellular biology. Their connection to metabolism is particularly significant, as it plays a critical role in energy regulation and distribution within organisms. Over recent decades, metabolism has emerged as a relevant focus in studies of biological regulation, especially following its recognition as a hallmark of cancer. This shift has broadened cancer research beyond strictly genetic perspectives. The interaction between metabolism and redox systems in carcinogenesis involves the regulation of essential metabolic pathways, such as glycolysis and the Krebs cycle, as well as the involvement of redox-active components like specific amino acids and cofactors. The feedback mechanisms linking redox systems and metabolism in cancer highlight the development of redox patterns that enhance the flexibility and adaptability of tumor processes, influencing larger-scale biological phenomena such as circadian rhythms and epigenetics.

Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation. In recent years, the focus of cancer metabolic research has shifted from the regulation and utilization of cancer cell-intrinsic pathways to studying how the metabolic landscape of the tumor affects the anti-tumor immune response. Recent discoveries point to the role that secreted metabolites within the TME play in crosstalk between tumor cell types to promote tumorigenesis and hinder the anti-tumor immune response. In this review, we will explore how crosstalk between metabolites of cancer cells, immune cells, and stromal cells drives tumorigenesis and what effects the competition for resources and metabolic crosstalk has on immune cell function.

Pancreatic ductal adenocarcinoma (PDAC) is remarkably resistant to standard modalities, including radiotherapy. We hypothesized that metabolic reprogramming may underlie PDAC radioresistance, and moreover, that it would be possible to exploit these metabolic changes for therapeutic intent.

We established two matched models of radioresistant PDAC cells by exposing the AsPC-1 and MIAPaCa-2 human pancreatic cancer cells to incremental doses of radiation. The metabolic profile of parental and radioresistant cells was investigated using Nanostring technology, labeled-glucose tracing by liquid chromatography-mass spectrometry, Seahorse analysis and exposure to metabolic inhibitors. The synergistic effect of radiation combined with a pentose-phosphate pathway inhibitor, 6-aminonicotinamide (6-AN) was evaluated in a xenograft model established by subcutaneous injection of radioresistant-AsPC-1 cells into nude mice.

The radioresistant cells overexpressed pyruvate dehydrogenase kinase (PDK) and consistently, displayed increased glycolysis and downregulated the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Metabolic flux through the pentose-phosphate pathway (PPP) was increased, as were levels of reduced glutathione; pharmacological inhibition of the PPP dramatically potentiated radiation-induced cell death. Furthermore, the combined treatment of radiation with the PPP inhibitor 6-AN synergistically inhibited tumor growth in-vivo.

We provide a mechanistic understanding of the metabolic changes that underlie radioresistance in PDAC. Furthermore, we demonstrate that pancreatic cancer cells can be re-sensitized to radiation via metabolic manipulation, in particular, inhibition of the PPP. Exploitation of the metabolic vulnerabilities of radioresistant pancreatic cancer cells constitutes a new approach to pancreatic cancer, with a potential to improve clinical outcomes.

Pancreatic ductal adenocarcinoma (PDAC) exhibits an altered metabolic profile compared to normal pancreatic tissue. However, studies on actual pancreatic tissues are limited. Untargeted metabolomics analysis was conducted on 54 pairs of tumor and matched normal tissues. Taurine levels were validated via immunohistochemistry (IHC) on separate PDAC and normal tissues. Bioinformatics analysis of transcriptomics and proteomics data evaluated genes associated with taurine metabolism. Identified taurine-associated gene was validated through gene modulation. Clinical implications were evaluated using patient data. Metabolomics analysis showed a 2.51-fold increase in taurine in PDAC compared to normal tissues (n=54). IHC confirmed this in independent samples (n=99 PDAC, 19 normal). Bioinformatics identified 2-aminoethanethiol dioxygenase (ADO) as a key gene modulating taurine metabolism. IHC on a tissue microarray (39 PDAC, 10 normal) confirmed elevated ADO in PDAC. The ADO-Taurine axis correlated with PDAC recurrence and disease-free survival. ADO knockdown reduced cancer cell proliferation and tumor growth in a mouse xenograft model. The MEK-related signaling pathway is suggested to be modulated by ADO-Taurine metabolism. Our multi-omics investigation revealed elevated taurine synthesis mediated by ADO upregulation in PDAC. The ADO-Taurine axis may serve as a biomarker for PDAC prognosis and a therapeutic target.

Although gemcitabine (GEM) is the cornerstone of the treatment of pancreatic cancer (PC), GEM resistance frequently arises. Circular RNA (circRNA) circ_0075829 is highly expressed in PC. However, whether circ_0075829 contributes to GEM resistance of PC is largely unknown. To generate GEM-resistant PC cells (BxPC-3/GR and SW1990/GR), we exposed GEM-sensitive PC cells to GEM. Circ_0075829, microRNA (miR)-326, and glutamic-oxaloacetic transaminase 1 (GOT1) were quantified by a qRT-PCR or western blot method. Cell survival and viability were gauged by MTS assay. Cell proliferation, apoptosis, invasion, and migration were assessed by EdU, flow cytometry, transwell, and wound-healing assays, respectively. Dual-luciferase reporter assays were used to verify the relationship between miR-326 and circ_0075829 or GOT1. Mouse xenografts were performed to evaluate the role of circ_0075829 in vivo. Our data showed that circ_0075829 was upregulated in GEM-resistant PC tissues and cells. Knockdown of circ_0075829 impeded the proliferation, invasion, migration, and glutamine metabolism, and promoted cell apoptosis and GEM sensitivity of GEM-resistant PC cells. Moreover, circ_0075829 silencing suppressed the tumorigenicity of SW1990/GR cells and sensitized them to the cytotoxic effect of GME in vivo. Mechanistically, circ_0075829 bound miR-326 and exerted regulatory effects by affecting miR-326 expression. GOT1 was a direct miR-326 target and a key downstream effector of miR-326. Furthermore, circ_0075829 modulated GOT1 expression via miR-326. Our findings establish a novel regulatory network, the circ_0075829/miR-326/GOT1 competing endogenous RNA (ceRNA) crosstalk, in the regulation of GEM resistance in PC.

Colorectal cancer (CRC) cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro-tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. Colorectal tumors with high glutaminase (GLS) expression exhibited reduced T cell infiltration and cytotoxicity, leading to poor clinical outcomes. However, depletion of GLS in CRC cells has minimal effect on tumor growth in immunocompromised mice. By contrast, remarkable inhibition of tumor growth is observed in immunocompetent mice when GLS is knocked down. It is found that GLS knockdown in CRC cells enhanced the cytotoxicity of tumor-specific T cells. Furthermore, the single-cell flux estimation analysis (scFEA) of glutamine metabolism revealed that glutamate-to-glutathione (Glu-GSH) flux, downstream of GLS, rather than Glu-to-2-oxoglutarate flux plays a key role in regulating the immune response of CRC cells in the tumor. Mechanistically, inhibition of the Glu-GSH flux activated reactive oxygen species (ROS)-related signaling pathways in tumor cells, thereby increasing the tumor immunogenicity by promoting the activity of the immunoproteasome. The combinatorial therapy of Glu-GSH flux inhibitor and anti-PD-1 antibody exhibited a superior tumor growth inhibitory effect compared to either monotherapy. Taken together, the study provides the first evidence pointing to Glu-GSH flux as a potential therapeutic target for CRC immunotherapy.

Colorectal Cancer (CRC) is the third most common cancer worldwide, and the occurrence and development of CRC are influenced by the molecular biology characteristics of CRC, especially alterations in key signaling pathways. The transforming growth factor-β (TGF-β) plays a crucial role in cellular growth, differentiation, migration, and apoptosis, with SMAD4 protein serving as a key transcription factor in the TGF-β signaling pathway, thus playing a significant role in the onset and progression of CRC. CRC is one of the malignancies with a high mortality rate worldwide. Despite significant research progress in recent years, especially regarding the role of SMAD4, its dual role in the early and late stages of tumor progression has promoted further discussion on its complexity as a therapeutic target, highlighting the urgent need for a deeper analysis of its role in CRC. This review aims to explore the function of SMAD4 protein in CRC and its potential as a therapeutic target.

Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development.

GOT1, a cytoplasmic glutamic oxaloacetic transaminase, plays a critical role in various metabolic pathways essential for cellular homeostasis and dysregulated metabolism. Recent studies have highlighted the significant plasticity and roles of GOT1 in metabolic reprogramming through participating in both classical and non-classical glutamine metabolism, glycolytic metabolism, and other metabolic pathways. This review summarizes emerging insights on the metabolic roles of GOT1 in cancer cells and emphasizes the response of cancer cells to altered metabolism when the expression of GOT1 is altered. We review how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT1 is inhibited and delineate the molecular mechanisms of GOT1's interaction with specific oncogenes and regulators at multiple levels, including transcriptional and epigenetic regulation, which govern cellular growth and metabolism. These insights may provide new directions for cancer metabolism research and novel targets for cancer treatment.