Cholangiocarcinoma (CCA) is an aggressive malignancy characterized by limited therapeutic options and poor prognosis, largely attributed to the presence of cancer stem cells (CSCs). These CSCs serve as pivotal drivers of tumor heterogeneity, chemotherapy resistance, and disease recurrence. CSCs in CCA exhibit remarkable plasticity, a characteristic sustained through metabolic state alterations and intricate interactions with the tumor microenvironment (TME), which collectively enhance their self-renewal and survival potential. While advancements have been made in understanding metabolic reprogramming of CCA CSCs, translating these findings into clinical applications encounters significant challenges, including insufficient target specificity, complex metabolic heterogeneity, and the profound complexity of the TME. This review provides a systematic evaluation of metabolic reprogramming mechanisms in CCA CSCs, with critical analysis of stemness-maintaining signaling pathways, oxidative phosphorylation (OXPHOS), nutrient utilization, metabolic crosstalk within the TME, autophagy regulation, and ferroptosis resistance. We emphasize emerging strategies to therapeutically target the interconnected metabolic networks essential for CSC functionality and survival, with the goal of establishing a theoretical basis for innovative precision therapies to enhance clinical outcomes for CCA patients.

Solute carrier family 27 member 5 (SLC27A5/FATP5) is a liver-specific metabolic enzyme that plays a crucial role in fatty acid transport and bile acid metabolism. Deficiency of SLC27A5 promotes the progression of hepatocellular carcinoma (HCC) and is strongly associated with a poor prognosis. SLC27A5 exhibits noncanonical functions beyond its metabolic role; however, its specific mechanisms in hepatocarcinogenesis remain elusive and are therefore investigated in this study. Immunoprecipitation-mass spectrometry analysis showed that SLC27A5-interacting proteins were significantly enriched in alternative polyadenylation (APA). RNA-sequencing data provided evidence that SLC27A5 plays a global role in regulating APA events in HCC. Mechanistically, SLC27A5 facilitates the usage of the proximal polyadenylation site of METTL14 by downregulating the expression of the APA-associated factor PABPC1, resulting in the shortening of the METTL14-3'UTR and the conversion of METTL14-UL to METTL14-US. In contrast to METTL14-UL, METTL14-US escapes the inhibitory effect of miRNA targeting, leading to increased METTL14 expression. METTL14-US upregulation by SLC27A5 suppressed the stemness of HCC. Therefore, low levels of SLC27A5 and METTL14 may serve as reliable biomarkers for identifying poor prognosis in patients with HCC. In conclusion, SLC27A5/PABPC1 inhibits HCC stemness via APA-regulated expression of METTL14, providing potential avenues for the development of novel therapeutic strategies.

The distinctive desmoplastic tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is crucial in determining the stemness of tumor cells. And the conventional two-dimensional (2D) culture does not adequately mimic the TME. Therefore, a three-dimensional (3D) PDAC desmoplastic model was constructed using GelMA and HAMA, which provides benefits in terms of simulating both the main components (COL and HA) and the crosslinking of the extracellular matrix. We found that the 3D PDAC desmoplastic model upregulated the expression of the markers for stemness (NANOG and OCT4) and glycolysis (HK2 and GLUT2), and elevated the level of glycolysis, including increased glucose consumption and lactic acid production. Additionally, YAP1 played a crucial role in promoting glycolysis, which boosted stemness. Furthermore, RNA sequencing (RNA-seq) was employed to explore the underlying mechanisms associated with stemness within the 3D desmoplastic model. Subsequent KEGG pathway analysis indicated the activation of the PI3K-AKT signaling pathway, providing insights into the molecular processes at play. Using bioinformatics, qRT-PCR and western blot, we proposed that ITGAV-PI3K-AKT-YAP1 axis may account for the glycolysis mediated the stemness. Collectively, the 3D desmoplastic model may serve as a new platform for understanding the underlying mechanism by which the TME induces stemness.

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.

Hepatoblastoma (HB) is the most common malignant liver tumor in children, with limited treatment options. The N4-acetylcytidine (ac4C) modification, an important mRNA post-transcriptional modification catalyzed by N-acetyltransferase 10 (NAT10), plays a crucial role in the initiation and progression of tumors. However, its impact on the development and prognosis of HB is largely unknown. This study demonstrates that NAT10 is notably upregulated in HB. NAT10 inhibition suppressed HB proliferation and metastasis in vitro and in vivo. Mechanistically, Yes-associated protein 1 (YAP1) induced NAT10 transcription by binding to its promoter, which stimulates the ac4C modification within the 3' untranslated region (3' UTR) of glucose-6-phosphate dehydrogenase (G6PD) and enhancing its mRNA stability. YAP1/NAT10/G6PD axis resulted in enhanced pentose phosphate pathway (PPP) to promote proliferation and metastasis of HB. Moreover, said NAT10-mediated oncogenic effect could be significantly attenuated by a NAT10 inhibitor (Remodelin) both in vitro experiments and in vivo HB mouse models. Overall, our findings revealed the oncogenic role of NAT10 in regulating HB growth and metastasis, which can be a potential therapeutic target for human HB.

Cell cycle progression is timely interconnected with oscillations in cellular metabolism. Here, we first describe how these metabolic oscillations allow cycling cells to meet the bioenergetic needs specifically for each phase of the cell cycle. In parallel, we highlight how the cytosolic level of citrate is dynamically regulated during these different phases, being low in G1 phase, increasing in S phase, peaking in G2/M, and decreasing in mitosis. Of note, in cancer cells, a dysregulation of such citrate oscillation can support cell cycle progression by promoting a deregulated Warburg effect (aerobic glycolysis), activating oncogenic signaling pathways (such as PI3K/AKT), and promoting acetyl-CoA production via alternative routes, such as overconsumption of acetate. Then, we review how administration of sodium citrate (at high doses) arrests the cell cycle in G0/G1 or G2/M, inhibits glycolysis and PI3K/AKT, induces apoptosis, and significantly reduces tumor growth in various in vivo models. Last, we reason on the possibility to implement citrate administration to reinforce the effectiveness of cell cycle inhibitors to better cure cancer.

This paper examined the role of solute carrier family 2 member 1 (SLC2A1) in colorectal cancer (CRC) progression, focusing on its expression levels, functional implications, and regulatory mechanisms involving Yes-associated protein 1 (YAP1) and the Wnt signaling pathway.

GEO datasets (GSE14297, GSE18462, GSE40367) were analyzed to identify genes linked to metastasis in CRC, and TCGA-COAD system was used to analyze the expression pattern and prognostic values of SLC2A1 in CRC. Functional studies were conducted using CRC cell lines (Caco-2 and SW480). Cell viability, migration and invasion, and apoptosis were examined using EdU assays, Transwell assays, and flow cytometry. YAP1's regulatory role on SLC2A1 was investigated using ChIP-qPCR and luciferase reporter assays. The Wnt/β-catenin agonist SKL2001 was used for functional rescue experiments.

SLC2A1 was upregulated in CRC cells, and its upregulation was associated with tumor metastasis and unfavorable outcomes according to bioinformatics. Knockdown of SLC2A1 resulted in reduced cell viability, decreased migration, and increased apoptosis in Caco-2 and SW480 cells. Additionally, YAP1 was identified as a transcriptional activator of SLC2A1. Knockdown of YAP1 decreased SLC2A1 expression and reduced expression of Wnt target genes, thus suppressing malignant behavior of tumor cells. However, further overexpression of SLC2A1 restored cell viability and migration in YAP1-deficient cells. The YAP1- SLC2A1 axis activated the Wnt/β-catenin by reducing GSK3β activity.

SLC2A1 is critical in CRC progression, with YAP1 serving as a key regulator of its expression and function. The YAP1-SLC2A1-Wnt axis represents a potential therapeutic target for CRC, providing insights into metabolic adaptations that support tumor growth and metastasis.

Glucose metabolic enzymes and their metabolites not only provide energy and building blocks for synthesizing macromolecules but also possess non-canonical or moonlighting functions in response to extracellular and intracellular signalling. These moonlighting functions modulate various cellular activities, including gene expression, cell cycle progression, DNA repair, autophagy, senescence and apoptosis, cell proliferation, remodelling of the tumour microenvironment and immune responses. These functions integrate glucose metabolism with other essential cellular activities, driving cancer progression. Targeting these moonlighting functions could open new therapeutic avenues and lead to cancer-specific treatments.

Lycium barbarum extracts have been shown to be effective in male reproductive protection and male infertility. However, its role in enhancing testicular function, such as testosterone synthesis, and the potential mechanism remain to be understood. To elucidate the effects of Lycium barbarum glycopeptide (LbGp) on testosterone synthesis, we isolated primary Leydig cells (LCs) from testes and performed RNA sequencing (RNA seq) on LCs treated with LbGp. In this study, we demonstrated that LbGp promoted testosterone synthesis in LCs both in vivo and in vitro. We also demonstrated that LbGp elevated adenosine 5'-triphosphate (ATP) synthesis and cell proliferation by enhancing glucose metabolism. Mechanistically, LbGp upregulated testosterone synthesis by suppressing TGF-β pathway and enhancing the expression of steroidogenic genes: Cyp11a1, Hsd3b1, Hsd17b3, Star, and Sf-1. These findings indicate that LbGp plays an important role in enhancing testicular function and promoting testosterone synthesis.

Lactate, once considered a mere byproduct of anaerobic metabolism, is now recognized as a critical signaling molecule with diverse roles in physiology and pathology. There are two stereoisomers of lactate: L- and D-lactate. Recent studies have shown that disruptions in these two lactate stereoisomers have distinct effects on health and disease. L-lactate is central to glycolysis and energy transfer through the Cori cycle but also acts as the dominant lactylation isomer induced by glycolysis, influencing metabolism and cell survival. Although less studied, D-lactate is linked to metabolic disorders and plays a role in mitochondrial dysfunction and oxidative stress. This review focuses on both L- and D-lactate and examines their biosynthesis, transport, and expanding roles in physiological and pathological processes, particularly their functions in cancer, immune regulation, inflammation, neurodegeneration and other diseases. Finally, we assess the therapeutic prospects of targeting lactate metabolism, highlighting emerging strategies for intervention in clinical settings. Our review synthesizes the current understanding of L- and D-lactate, offering insights into their potential as targets for therapeutic innovation.

Thyroid cancer as one of the most prevalent malignancies of endocrine system, has raised public concern and more research on its mechanism and treatment. And metabolism-based therapies have advanced rapidly, for the exclusive metabolic profiling of thyroid cancer. In thyroid cancer cells, plenty of metabolic pathways are reprogrammed to accommodate tumor microenvironment. In this review, we initiatively summarize recent progress in the full-scale thyroid cancer metabolic rewiring and the interconnection of various metabolites. We also discuss the efficacy and prospect of metabolic targeted detection as well as therapy. Comprehending metabolic mechanism and characteristics of thyroid cancer roundly will be highly beneficial to managing individual patients.

The identification of molecular features characterizing metastatic disease is a critical area of oncology research, as metastatic foci often exhibit distinct biological behaviors compared to primary tumors. While the focus has largely been on the neoplastic cells themselves, the characterization of the associated stroma remains largely underexplored, with significant implications for understanding metastasis.

By employing spatially resolved transcriptomics, we analyzed the transcriptional features of primary breast adenocarcinoma and its associated metastatic foci, on a representative set of microregions. We identified a stromal metastatic (Met) signature, which was subsequently validated across transcriptomic reference human breast cancer (BC) datasets and in spatial transcriptomics of a murine model.

We discuss the potential of a stromal Met signature to pinpoint metastatic breast cancer, serving as a prognostic tool that can provide a foundation for the exploration of tumor-extrinsic molecular hallmarks of BC metastatic foci.

Metabolic syndrome (MetS) has been associated with disruptions in tissue mechanical homeostasis and inflammatory and metabolic derangements. However, the direct correlation between metabolic alterations and changes in tissue stiffness, and whether they could play a role as upstream initiators of disease pathology remains to be investigated. This emerging concept has yet to be put into clinical practice as many questions concerning the interplay between extracellular matrix mechanical properties and regulation of metabolic pathways remain unsolved. This review will highlight key foundational studies examining mutual regulation of cell metabolism and mechanotransduction, and opening questions lying ahead for better understanding MetS pathophysiology.

Ferroptosis contributes to brain injury after germinal matrix hemorrhage (GMH). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, reduces oxidative stress in neurodegenerative diseases. In vitro, Deferiprone has been shown to upregulate FTMT. However, the effects of FTMT upregulation by Deferiprone on neuronal ferroptosis after GMH and its underlying mechanism has not been investigated. In our study, 389 Sprague-Dawley rat pups of postnatal day 7 were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. The brain expressions of FTMT, N-myc downstream-regulated gene-1 (NDGR1), Yes-associated protein (YAP), ferroptosis-related molecules including transferrin receptor (TFR) and acyl-CoA synthase long-chain family member 4 (ACSL4) were increased after GMH. FTMT agonist Deferiprone improved neurological deficits and hydrocephalus after GMH. Deferiprone or Adenovirus-FTMT enhanced YAP phosphorylation at the Ser127 site and attenuated ferroptosis, which was reversed by NDRG1 CRISPR Knockout. Iron overload induced neuronal ferroptosis and neurological deficits, which were improved by YAP CRISPR Knockout. Collectively, FTMT upregulation by Deferiprone reduced neuronal ferroptosis and neurological deficits via the NDRG1/YAP signaling pathway after GMH. Deferiprone may serve as a potential non-invasive treatment for GMH patients.

The rising trend in global cancer incidence has caused widespread concern, one of the main reasons being the aging of the global population. Statistical data show that cancer incidence and mortality rates show a clear upward trend with age. Although there is a commonality between dysregulated nutrient sensing, which is one of the main features of aging, and metabolic reprogramming of tumor cells, the specific regulatory relationship is not clear. This manuscript intends to comprehensively analyze the relationship between senescence and tumor metabolic reprogramming; as well as reveal the impact of key factors leading to cellular senescence on tumorigenesis. In addition, this review summarizes the current intervention strategies targeting nutrient sensing pathways, as well as the clinical cases of treating tumors targeting the characteristics of senescence with the existing nanodelivery research strategies. Finally, it also suggests sensible dietary habits for those who wish to combat aging. In conclusion, this review attempts to sort out the link between aging and metabolism and provide new ideas for cancer treatment.

Tumor metastasis regulated by multiple complicated pathways is closely related to variations in the tumor microenvironment. Exosomes can regulate the tumor microenvironment through various mechanisms. Exosomes derived from tumor cells carry a variety of substances, including long non-coding RNAs (lncRNAs), play important roles in intercellular communication and act as critical determinants influencing tumor metastasis. In this review, we elaborate on several pivotal processes through which lncRNAs regulate tumor metastasis, including the regulation of epithelial‒mesenchymal transition, promotion of angiogenesis and lymphangiogenesis, enhancement of the stemness of tumor cells, and evasion of immune clearance. Additionally, we comprehensively summarized a diverse array of potential tumor-derived exosomal lncRNA biomarkers to facilitate accurate diagnosis and prognosis in a clinical setting.

In triple-negative breast cancer (TNBC), pro-tumoral macrophages promote metastasis and suppress the immune response. To target these cells, a previously identified CD206 (mannose receptor)-binding peptide, mUNO was engineered to enhance its affinity and proteolytic stability. The new rationally designed peptide, MACTIDE, includes a trypsin inhibitor loop, from the Sunflower Trypsin Inhibitor-I. Binding studies to recombinant CD206 revealed a 15-fold lower KD for MACTIDE compared to parental mUNO. Mass spectrometry further demonstrated a 5-fold increase in MACTIDE's half-life in tumor lysates compared to mUNO. Homing studies in TNBC-bearing mice shows that fluorescein (FAM)-MACTIDE precisely targeted CD206+ tumor-associated macrophages (TAM) upon intravenous, intraperitoneal, and even oral administration, with minimal liver accumulation. MACTIDE was conjugated to Verteporfin, an FDA-approved photosensitizer and YAP/TAZ pathway inhibitor to create the conjugate MACTIDE-V. In the orthotopic 4T1 TNBC mouse model, non-irradiated MACTIDE-V-treated mice exhibited anti-tumoral effects comparable to those treated with irradiated MACTIDE-V, with fewer signs of toxicity, prompting further investigation into the laser-independent activity of the conjugate. In vitro studies using bone marrow-derived mouse macrophages showed that MACTIDE-V excluded YAP from the nucleus, increased phagocytic activity, and upregulated several genes associated with cytotoxic anti-tumoral macrophages. In mouse models of TNBC, MACTIDE-V slowed primary tumor growth, suppressed lung metastases, and increased markers of phagocytosis and antigen presentation in TAM and monocytes, increasing the tumor infiltration of several lymphocyte subsets. MACTIDE-V is proposed as a promising peptide-drug conjugate for modulating macrophage function in breast cancer immunotherapy.

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.

Energy metabolism plays a pivotal role in cancer clinical treatment and has become an important means of clinical diagnosis of tumour progression. However, current research mostly focuses on changes in metabolic products and neglects the deeper mechanisms of transcriptional regulation. This paper proposes a new perspective, establishing a comprehensive network that reveals the interaction between metabolism and transcription, which explores how tumour metabolism affects tumour progression through transcriptional modifications, and provides a novel approach for optimizing tumour treatment strategies. This viewpoint is conducive to overcoming current bottlenecks in treatment and promoting the development of drug combinations and personalized medicine.

Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.

Glycolysis, present in most organisms, is evolutionarily one of the oldest metabolic pathways. It has great relevance at a physiological level because it is responsible for generating ATP in the cell through the conversion of glucose into pyruvate and reducing nicotinamide adenine dinucleotide (NADH) (that may be fed into the electron chain in the mitochondria to produce additional ATP by oxidative phosphorylation), as well as for producing intermediates that can serve as substrates for other metabolic processes. Glycolysis takes place through 10 consecutive chemical reactions, each of which is catalysed by a specific enzyme. Although energy transduction by glucose metabolism is the main function of this pathway, involvement in virulence, growth, pathogen-host interactions, immunomodulation and adaptation to environmental conditions are other functions attributed to this metabolic pathway. In humans, where glycolysis occurs mainly in the cytosol, the mislocalization of some glycolytic enzymes in various other subcellular locations, as well as alterations in their expression and regulation, has been associated with the development and progression of various diseases. In this review, we describe the role of glycolytic enzymes in the pathogenesis of diseases of clinical interest. In addition, the potential role of these enzymes as targets for drug development and their potential for use as diagnostic and prognostic markers of some pathologies are also discussed.

Targeting glucose uptake by glucose transporter (GLUT) inhibitors is a therapeutic opportunity, but efforts on GLUT inhibitors have not been successful in the clinic and the underlying mechanism remains unclear. We aim to identify the key metabolic changes responsible for cancer cell survival from glucose limitation and elucidate its mechanism.

The level of phosphorylated YAP was analyzed with Western blotting and Phos-tag immunoblotting. Glucose limitation-induced metabolic changes were analyzed using targeted metabolomics (600MRM). The anti-cancer role of metabolite was examined using colony formation assay and APCmin/+ mice. Co-immunoprecipitation, LS-MS, qRT-PCR, and immunofluorescence were performed to explore the underlying mechanisms.

We found that D-Ribose-5-phosphate (D5P), a product of the pentose phosphate pathway connecting glucose metabolism and nucleotide metabolism, functions as a metabolic checkpoint to activate YAP under glucose limitation to promote cancer cell survival. Mechanistically, in glucose-deprived cancer cells, D5P is decreased, which facilitates the interaction between MYH9 and LATS1, resulting in MYH9-mediated LATS1 aggregation, degradation, and further YAP activation. Interestingly, activated YAP further promotes purine nucleoside phosphorylase (PNP)-mediated breakdown of purine nucleoside to restore D5P in a feedback manner. Importantly, D5P synergistically enhances the tumor-suppressive effect of GLUT inhibitors and inhibits cancer progression in mice.

Our study identifies D5P as a metabolic checkpoint linking glucose limitation stress and YAP activation, indicating that D5P may be a potential anti-cancer metabolite by enhancing glucose limitation sensitivity.

Metabolic reprogramming fuels cancer cell metastasis and remodels the immunosuppressive tumor microenvironment (TME). We report here that circPETH, a circular RNA (circRNA) transported via extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis in recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in an m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via the MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by increasing HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8+ T cells. Importantly, through virtual and experimental screening, we find that a small molecule, Norathyriol, is an effective inhibitor that targets the MEG pocket on the circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes by HCC cells, increases anti-PD1 efficacy, and enhances cytotoxic CD8+ T-cell function. Here we show that Norathyriol is a promising anti-HCC agent that contributes to attenuating the resistance of advanced HCC to immune checkpoint blocker (ICB) therapies.

Immunotherapy, either alone or in combination with chemotherapy, has demonstrated limited efficacy in a variety of solid cancers. Several factors contribute to explaining primary or secondary resistance. Among them, cancer cells, whose metabolism frequently relies on aerobic glycolysis, promote exhaustion of cytotoxic immune cells by diverting the glucose in the tumor microenvironment (TME) to their own profit, while secreting lactic acid that sustains the oxidative metabolism of immunosuppressive cells. Here, we propose to combine current treatment based on the use of immune checkpoint inhibitors (ICIs) with high doses of sodium citrate (SCT) because citrate inhibits cancer cell metabolism (by targeting both glycolysis and oxidative metabolism) and may active anti-tumor immune response. Indeed, as showed in preclinical studies, SCT reduces cancer cell growth, promoting cell death and chemotherapy effectiveness. Furthermore, since the plasma membrane citrate carrier pmCIC is mainly expressed in cancer cells and low or not expressed in immune and non-transformed cells, we argue that the inhibition of cancer cell metabolism by SCT may increase glucose availability in the TME, thus promoting functionality of anti-tumor immune cells. Concomitantly, the decrease in the amount of lactic acid in the TME may reduce the functionality of immunosuppressive cells. Preclinical studies have shown that SCT can enhance the anti-tumor immune response through an enhancement of T cell infiltration and activation, and a repolarization of macrophages towards a TAM1-like phenotype. Therefore, this simple and cheap strategy may have a major impact to increase the efficacy of current immunotherapies in human solid tumors and we encourage testing it in clinical trials.

Hypoxia is known to induce reprogramming of glucose metabolism in cancer. However, the impact of hypoxia on global metabolism remains poorly understood. Here, using the systems approach, we evaluated the potential crosstalk between hypoxia and global metabolism using data from > 2000 breast tumors. Tumor samples were scored for hypoxia and 90 metabolic pathways, and these metrics were subjected to an analysis pipeline. Hypoxia showed a very strong association with metabolic aggression and an overall contextual relationship with metabolism. Out of three (M1, M2, and M3) metabolic types in breast cancer, M3 exhibited the strongest relationship with hypoxia; that is, high hypoxic tumors were also metabolically deregulated. Further, the overall correlation pattern between hypoxia and metabolic pathway scores was specific to each type, with M1 showing maximal sensitivity to hypoxia, followed by M2 and then M3. Experimental validation using metabolic inhibitors on cell lines with high or low hypoxia scores further confirmed the metabolic type-dependence of hypoxia. In addition, evaluation of the impact of hypoxia on cancer pathways other than metabolic ones revealed a potential role of hypoxia in immune evasive characteristic of M3 tumors. Overall, the results suggest a complex interplay between hypoxia and metabolism in the context of human breast tumors, with potential implications for both basic cancer biology and breast cancer therapy.

Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance-YAP/TAZ, SREBP1/2 and NRF2-to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity-hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.

Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as "moonlighting" functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to α-ketoglutarate in cells. However, research on IDH1 is more focused on the metabolite D-2-hydroxyglutarate than the cellular roles of the IDH1 protein. Metabolic enzymes can moonlight by participating in diverse cellular processes in cancer cells. This moonlighting function of the metabolic enzymes can contribute to changes in gene expression. It is unknown whether IDH1 associates with any transcription factor. We asked whether IDH1 coordinates with forkhead box protein M1 (FOXM1) in mitotic cells to regulate late genes expression. We found that depletion of IDH1 reduces canonical FOXM1-target expression in mitotic cells. Also, IDH1 binds to FOXM1 and a subset of MuvB proteins, Lin-9 and Lin-54, in mitotic cells. Based on these observations, we suggest that IDH1 coordinates with FOXM1 in mitotic cells to regulate late genes expression.

Increased levels of lactoferrin (Lf) are present in the aged brain and in the lesions of various neurodegenerative diseases, including Parkinson's disease (PD), and may contribute to the cascade of events involved in neurodevelopment and neuroprotection. However, whether Lf originates from astrocytes and functions within either the normal or pathological brain are unknown. Here, we employed mice with specific knockout of the astrocyte lactoferrin gene (named Lf-cKO) to explore its specific roles in the pathological process of PD. We observed a decrease in tyrosine hydroxylase-positive cells, mitochondrial dysfunction of residual dopaminergic neurons, and motor deficits in Lf-cKO mice, which were significantly aggravated after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. To further explore how astrocytic lactoferrin deficiency exacerbated PD-like manifestation in MPTP-treated mice, the critical molecules involved in endoplasmic reticulum (ER)-mitochondria contacts and signaling pathways were investigated. In vitro and in vivo models, we found an aberrant level of effects implicated in glutamate and calcium homeostasis, mitochondrial morphology and functions, mitochondrial dynamics, and mitochondria-associated ER membranes, accompanied by signs of oxidative stress and ER stress, which increase the fragility of dopaminergic neurons. These findings confirm the existence of astrocytic Lf and its influence on the fate of dopaminergic neurons by regulating glutamate/calcium metabolism and ER-mitochondria signaling. Our findings may be a promising target for the treatment of PD.

THCA (Thyroid carcinoma) is the most common endocrine malignancy in the world. The PLOD1 is highly expressed in THCA, but the mechanism is still unclear. It is found that the cell proliferation and migration were inhibited in si-PLOD1 group, and promoted with PLOD1 overexpression. MAZ is the transcription factor of PLOD1. The cell activities induced MAZ were reversed by si-PLOD1. The Glucose uptake, lactate production and ATP/ADP ratio were decreased with si-PLOD1. The glycolysis related proteins GLUT1, HK2, PFKP, PKM2, LDHA and Wnt/β-catenin pathway proteins WNT5A, cyclin D1, β-catenin were inhibited, GSK-3β is increased in si-PLOD1 group. BML-284 could reversed the si-PLOD1 effects on cell activities and Wnt/β-catenin pathway. The tumor xenografts were inhibited in si-PLOD1 group. As a potential therapeutic target, PLOD1 is regulated by MAZ in THCA. PLOD1 depletion could inhibit THCA cell proliferation and metastasis by glycolysis, which is inhibited by Wnt/β-catenin pathway in THCA.

Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn't induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.

Osteosarcoma, recognized for its aggressiveness and resistance to chemotherapy, notably doxorubicin, poses significant treatment challenges. This comprehensive study investigated the CXCR4-CARM1-YAP signaling axis and its pivotal function in controlling aerobic glycolysis, which plays a crucial role in doxorubicin resistance. Detailed analysis of Dox-resistant 143b/MG63-DoxR cells has uncovered the overexpression of CXCR4. Utilizing a combination of molecular biology techniques including gene silencing, aerobic glycolysis assays such as Seahorse experiments, RNA sequencing, and immunofluorescence staining. The study provides insight into the mechanistic pathways involved. Results demonstrated that disrupting CXCR4 expression sensitizes cells to doxorubicin-induced apoptosis and alters glycolytic activity. Further RNA sequencing revealed that CARM1 modulated this effect through its influence on glycolysis, with immunofluorescence of clinical samples confirming the overexpression of CXCR4 and CARM1 in drug-resistant tumors. Chromatin immunoprecipitation studies further highlighted the role of CARM1, showing it to be regulated by methylation at the H3R17 site, which in turn affected YAP expression. Crucially, in vivo experiments illustrated that CARM1 overexpression could counteract the tumor growth suppression that resulted from CXCR4 inhibition. These insights revealed the intricate mechanisms at play in osteosarcoma resistance to doxorubicin and pointed toward potential new therapeutic strategies that could target this metabolic and signaling network to overcome drug resistance and improve patient outcomes.

In recent years, metabolic reprogramming in liver fibrosis has become a research hotspot in the field of liver fibrosis at home and abroad. Liver fibrosis is a pathological change caused by chronic liver injury from a variety of causes. Liver fibrosis is a common pathological feature of many chronic liver diseases such as chronic hepatitis B, non-alcoholic steatohepatitis, and autoimmune hepatitis, as well as the pathogenesis of the disease. The development of chronic liver disease into cirrhosis must go through the pathological process of liver fibrosis, in which hepatic stellate cells (HSC) play an important role. Following liver injury, HSC are activated and transdifferentiated into scar-forming myofibroblasts, which drive the trauma healing response and which rely on the deposition of collagen-rich extracellular matrix to maintain tissue integrity. This reaction will continue without strict control, which will lead to excessive accumulation of matrix and liver fibrosis. The mechanisms and clinical studies of liver fibrosis have been the focus of research in liver diseases. In recent years, several studies have revealed the mechanism of HSC metabolic reprogramming and the impact of this process on liver fibrosis, in which glucose metabolic reprogramming plays an important role in the activation of HSC, and it mainly meets the energy demand of HSC activation by upregulating glycolysis. Glycolysis is the process by which one molecule of glucose is broken down into two molecules of pyruvate and produces energy and lactate under anaerobic conditions. Various factors have been found to be involved in regulating the glycolytic process of HSC, including glucose transport, intracellular processing of glucose, exosome secretion, and lactate production, etc. Inhibition of the glycolytic process of HSC can be an effective strategy against liver fibrosis. Currently, the combined action of multiple targets and links of Chinese medicine such as turmeric, comfrey, rhubarb and scutellaria baicalensis against the mechanism of liver fibrosis can effectively improve or even reverse liver fibrosis. This paper summarizes that turmeric extract curcumin, comfrey extract comfreyin, rhubarb, Subtle yang yu yin granules, Scutellaria baicalensis extract oroxylin A and cardamom extract cardamomin affect liver fibrosis by regulating gluconeogenic reprogramming. Therefore, studying the mechanism of action of TCM in regulating liver fibrosis through reprogramming of glucose metabolism is promising to explore new methods and approaches for Chinese Medicine modernization research.

In this review, we explore the intricate relationship between glucose metabolism and mechanotransduction pathways, with a specific focus on the role of the Hippo signaling pathway in chondrocyte pathophysiology. Glucose metabolism is a vital element in maintaining proper chondrocyte function, but it has also been implicated in the pathogenesis of osteoarthritis (OA) via the induction of pro-inflammatory signaling pathways and the establishment of an intracellular environment conducive to OA. Alternatively, mechanotransduction pathways such as the Hippo pathway possess the capacity to respond to mechanical stimuli and have an integral role in maintaining chondrocyte homeostasis. However, these mechanotransduction pathways can be dysregulated and potentially contribute to the progression of OA. We discussed how alterations in glucose levels may modulate the Hippo pathway components via a variety of mechanisms. Characterizing the interaction between glucose metabolism and the Hippo pathway highlights the necessity of balancing both metabolic and mechanical signaling to maintain chondrocyte health and optimal functionality. Furthermore, this review demonstrates the scarcity of the literature on the relationship between glucose metabolism and mechanotransduction and provides a summary of current research dedicated to this specific area of study. Ultimately, increased research into this topic may elucidate novel mechanisms and relationships integrating mechanotransduction and glucose metabolism. Through this review we hope to inspire future research into this topic to develop innovative treatments for addressing the clinical challenges of OA.

Pulmonary fibrosis (PF) is a severe, irreversible lung disease characterized by progressive scarring, with idiopathic pulmonary fibrosis (IPF) being the most prevalent form. IPF's pathogenesis involves repetitive lung epithelial injury leading to fibroblast activation and excessive extracellular matrix (ECM) deposition. The prognosis for IPF is poor, with limited therapeutic options like nintedanib and pirfenidone offering only modest benefits. Emerging research highlights the dysregulation of the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway as a critical factor in PF. YAP and TAZ, components of the Hippo pathway, play significant roles in cell proliferation, differentiation, and fibrosis by modulating gene expression through interactions with TEA domain (TEAD) transcription factors. The aberrant activation of YAP/TAZ in lung tissue promotes fibroblast activation and ECM accumulation. Targeting the YAP/TAZ pathway offers a promising therapeutic avenue. Preclinical studies have identified potential treatments, such as trigonelline, dopamine receptor D1 (DRD1) agonists, and statins, which inhibit YAP/TAZ activity and demonstrate antifibrotic effects. These findings underscore the importance of YAP/TAZ in PF pathogenesis and the potential of novel therapies aimed at this pathway, suggesting a new direction for improving IPF treatment outcomes. Further research is needed to validate these approaches and translate them into clinical practice.