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Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a source of nitrogen for amino acid and nucleotide synthesis. To date, many studies have explored the role of glutamine metabolism in cancer, thereby providing a scientific rationale for targeting glutamine metabolism for cancer treatment. In this review, we summarize the mechanism(s) involved at each step of glutamine metabolism, from glutamine transporters to redox homeostasis, and highlight areas that can be exploited for clinical cancer treatment. Furthermore, we discuss the mechanisms underlying cancer cell resistance to agents that target glutamine metabolism, as well as strategies for overcoming these mechanisms. Finally, we discuss the effects of glutamine blockade on the tumor microenvironment and explore strategies to maximize the utility of glutamine blockers as a cancer treatment. Cancer: Targeting glutamine metabolism as potential treatment Further insights into metabolic reprogramming by cancer cells are needed to determine if targeting glutamine metabolism could be a useful therapeutic approach. Cancer cells rely on the amino acid glutamine for growth and proliferation. Glutamine is a key nitrogen source and enables the cells to synthesize critical molecules including lipids and metabolites. Blocking glutamine metabolism may be useful in treating cancers, but care must be taken due to glutamine’s multiple roles. Keun-Gyu Park and Yeon-Kyung Choi at Kyungpook National University in Daegu, South Korea, and co-workers reviewed current knowledge of the steps involved in glutamine metabolism to identify opportunities for intervention. Cancers can evade glutamine metabolism inhibition by manipulating the tumor microenvironment and finding alternative ways to source nutrients. Drug trials have targeted aspects of glutamine metabolism with mixed success, inhibition of glutamine transporters showing promise.

Background Macropinocytosis, an important nutrient-scavenging pathway in certain cancer cells, allows cells to compensate for intracellular amino acid deficiency under nutrient-poor conditions. Ferroptosis caused by cysteine depletion plays a pivotal role in sorafenib responses during hepatocellular carcinoma (HCC) therapy. However, it is not known whether macropinocytosis functions as an alternative pathway to acquire cysteine in sorafenib-treated HCC, and whether it subsequently mitigates sorafenib-induced ferroptosis. This study aimed to investigate whether sorafenib drives macropinocytosis induction, and how macropinocytosis confers ferroptosis resistance on HCC cells. Methods Macropinocytosis, both in HCC cells and HCC tissues, was evaluated by measuring TMR-dextran uptake or lysosomal degradation of DQ-BSA, and ferroptosis was evaluated via C11-BODIPY fluorescence and 4-HNE staining. Sorafenib-induced ferroptosis and macropinocytosis were validated in tumor tissues taken from HCC patients who underwent ultrasound-guided needle biopsy. Results Sorafenib increased macropinocytosis in human HCC specimens and xenografted HCC tissues. Sorafenib-induced mitochondrial dysfunction was responsible for activation of PI3K-RAC1-PAK1 signaling, and amplified macropinocytosis in HCC. Importantly, macropinocytosis prevented sorafenib-induced ferroptosis by replenishing intracellular cysteine that was depleted by sorafenib treatment; this rendered HCC cells resistant to sorafenib. Finally, inhibition of macropinocytosis by amiloride markedly enhanced the anti-tumor effect of sorafenib, and sensitized resistant tumors to sorafenib. Conclusion In summary, sorafenib induced macropinocytosis, which conferred drug resistance by mitigating sorafenib-induced ferroptosis. Thus, targeting macropinocytosis is a promising therapeutic strategy to facilitate ferroptosis-based therapy for HCC. Graphic Abstract

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC. Glutamine metabolism in TAMs: targeting HIF-1α translation for HCC This research examines how a substance derived from glutamine (an amino acid) called aspartate influences tumor-associated macrophages (TAMs - immune cells found in many cancers). Led by Dr. Keun-Gyu Park, the team discovered that aspartate from glutamine encourages TAMs to support the growth of hepatocellular carcinoma (HCC - a liver cancer). This process is aided by a protein, eIF5A. The team performed tests on mice and human cells and studied tissue samples from HCC patients. They discovered that blocking eIF5A’s function in TAMs could halt tumor growth. The research suggests that focusing on this metabolic process in TAMs could be a potential treatment strategy for HCC. The results also hint at possible future applications for treating other cancers. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

A growing body of evidence suggests that hyperglycemia-induced oxidative stress plays an important role in diabetic complications, especially β-cell dysfunction and failure. Under physiological conditions, reactive oxygen species serve as second messengers that facilitate signal transduction and gene expression in pancreatic β-cells. However, under pathological conditions, an imbalance in redox homeostasis leads to aberrant tissue damage and β-cell death due to a lack of antioxidant defense systems. Taking into account the vulnerability of islets to oxidative damage, induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed as a way to protect β-cells against diabetic insults. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions, as well as the therapeutic benefits of antioxidants, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with β-cell failure.

Recently, ferroptosis has emerged as a pathogenic mechanism that drives metabolic dysfunction-associated steatohepatitis (MASH); however, the upstream triggers and their relevance to fibrosis remain poorly understood. Here we identified dietary cholesterol-induced ferroptosis and the downregulation of peroxisome proliferator-activated receptor delta (PPARδ) as central drivers of MASH pathogenesis. To investigate this, human liver samples and cholesterol-enriched dietary murine models of MASH were examined in parallel with mechanistic studies in hepatocytes and hepatic stellate cells (HSCs). Cholesterol-induced MASH was associated with pronounced hepatic lipid peroxidation and the selective downregulation of PPARδ. The loss of PPARδ disrupted redox homeostasis and sensitized hepatocytes to ferroptosis, whereas exosomal double-stranded DNA released from ferroptotic hepatocytes activated STING–TBK1–IRF3 and induced expression of profibrotic genes in HSCs. These effects were reversed by either overexpression of hepatocyte-specific PPARδ or pharmacologic treatment with DN203316, a novel and highly selective PPARδ agonist. In vivo, DN203316 mitigated ferroptosis, inflammation and fibrosis without inducing metabolic derangement. These findings were substantiated by clinical data demonstrating a marked increase in lipid peroxidation and STING-driven HSC activation in liver tissues from patients with MASH. In conclusion, PPARδ is a key regulator of cholesterol-induced ferroptosis and exosome-mediated fibrogenic signaling in MASH. DN203316 offers a promising therapeutic strategy to suppress ferroptosis, disrupt hepatocyte–HSC crosstalk and attenuate disease progression. Cholesterol triggers ferroptosis and fibrosis in liver disease Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of liver disease characterized by inflammation and fibrosis, driven by complex metabolic and cellular interactions. This study identifies ferroptosis, a form of cell death linked to lipid peroxidation, as a key mechanism in MASH progression, highlighting the role of peroxisome proliferator-activated receptor delta (PPARδ) in regulating this process. Researchers used human liver samples and mouse models to demonstrate that cholesterol-induced ferroptosis in hepatocytes leads to the release of exosomal DNA, activating fibrogenic pathways in hepatic stellate cells. They found that the downregulation of PPARδ exacerbates ferroptosis, whereas its activation, through genetic overexpression or the novel agonist DN203316, mitigates liver damage by enhancing antioxidant defenses. These findings suggest that targeting PPARδ could offer a new therapeutic strategy for MASH, with DN203316 showing potential as a treatment to reduce liver fibrosis and inflammation. Future research could explore the broader implications of PPARδ modulation in metabolic liver diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Several intervention studies have suggested that vegetarian or vegan diets have clinical benefits, particularly in terms of glycemic control, in patients with type 2 diabetes (T2D); however, no randomized controlled trial has been conducted in Asians who more commonly depend on plant-based foods, as compared to Western populations. Here, we aimed to compare the effect of a vegan diet and conventional diabetic diet on glycemic control among Korean individuals. Participants diagnosed with T2D were randomly assigned to follow either a vegan diet (excluding animal-based food including fish; n = 46) or a conventional diet recommended by the Korean Diabetes Association 2011 (n = 47) for 12 weeks. HbA1c levels were measured at weeks 0, 4, and 12, and the primary study endpoint was the change in HbA1c levels over 12 weeks. The mean HbA1c levels at weeks 0, 4, and 12 were 7.7%, 7.2%, and 7.1% in the vegan group, and 7.4%, 7.2%, and 7.2% in the conventional group, respectively. Although both groups showed significant reductions in HbA1C levels, the reductions were larger in the vegan group than in the conventional group (-0.5% vs. -0.2%; p-for-interaction = 0.017). When only considering participants with high compliance, the difference in HbA1c level reduction between the groups was found to be larger (-0.9% vs. -0.3%). The beneficial effect of vegan diets was noted even after adjusting for changes in total energy intake or waist circumference over the 12 weeks. Both diets led to reductions in HbA1c levels; however, glycemic control was better with the vegan diet than with the conventional diet. Thus, the dietary guidelines for patients with T2D should include a vegan diet for the better management and treatment. However, further studies are needed to evaluate the long-term effects of a vegan diet, and to identify potential explanations of the underlying mechanisms. CRiS KCT0001771.

Background: Vascular smooth muscle cells (VSMCs) play a crucial role in the development of occlusive vascular diseases through abnormal proliferation and migration. This pathological behavior is closely associated with mitochondrial reactive oxygen species (ROS)-mediated mitochondrial DNA (mtDNA) damage. The mitochondrial carrier protein solute carrier family 25 member 33 (SLC25A33), essential for nucleoside transport, is integral to mtDNA production. This study aimed to investigate the effects of SLC25A33 inhibition on the proliferation and migration of VSMCs, as well as its impact on neointima formation.Methods: VSMCs were isolated from the thoracic aorta of 4-week-old Sprague-Dawley rats. The effects of small interfering RNAinduced silencing of SLC25A33 mRNA on platelet-derived growth factor (PDGF)-induced proliferation and migration of VSMCs were analyzed. The in vivo effects of targeting the SLC25A33 gene on neointima formation were evaluated using a murine carotid artery ligation model by perivascularly applying Lenti-shSLC25A33 with Pluronic F-127 gel.Results: First, we observed an upregulation of the SLC25A33 protein in the carotid artery ligation-induced neointima in mice. Silencing of SLC25A33 suppressed the PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Knockdown of SLC25A33 inhibited PDGF-induced production of mtDNA and ROS, consequently inactivating the cyclic GMP-AMP synthesis (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1)-nuclear factor kappa B (NF-κB) pathway. Furthermore, the downregulation of SLC25A33 reduced carotid artery ligation-induced neointima in mice.Conclusion: This study suggests that targeting SLC25A33 in VSMCs could be a novel therapeutic strategy to prevent occlusive vascular diseases.

Background: The Chinese visceral adiposity index (CVAI) and new visceral adiposity index (NVAI) are novel indices of visceral adiposity used to predict metabolic and cardiovascular diseases in Asian populations. However, the relationships of CVAI and NVAI with chronic kidney disease (CKD) have not been investigated. We aimed to characterize the relationships of CVAI and NVAI with the prevalence of CKD in Korean adults.Methods: A total of 14,068 participants in the 7th Korea National Health and Nutrition Examination Survey (6,182 men and 7,886 women) were included. Receiver operating characteristic (ROC) analyses were employed to compare the associations between indices of adiposity and CKD, and a logistic regression model was used to characterize the relationships of CVAI and NVAI with CKD prevalence.Results: The areas under the ROC curves for CVAI and NVAI were significantly larger than for the other indices, including the visceral adiposity index and lipid accumulation product, in both men and women (all P<0.001). In addition, high CVAI or NVAI was significantly associated with a high CKD prevalence in both men (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.31 to 3.48 in CVAI and OR, 6.47; 95% CI, 2.91 to 14.38 in NVAI, P<0.05) and women (OR, 4.87; 95% CI, 1.85 to 12.79 in CVAI and OR, 3.03; 95% CI, 1.35 to 6.82 in NVAI, P<0.05); this association remained significant after adjustment for multiple confounding factors in men and women.Conclusion: CVAI and NVAI are positively associated with CKD prevalence in a Korean population. CVAI and NVAI may be useful for the identification of CKD in Asian populations, including in Korea.

Background Oncogenic KRAS mutations in cancer cells drive macropinocytosis, a pathway that scavenges extracellular proteins to obtain nutrients under metabolic stress. Lysosomal degradation is essential for processing these proteins, but the precise molecular link between macropinocytic uptake and lysosomal processing remains largely unclear. Aldolase A (ALDOA), a glycolytic enzyme, has diverse non-canonical functions. While interactions between ALDOA and Vacuolar-type H⁺-ATPase (V-ATPase) subunits have been suggested, their functional role in lysosomal degradation of macropinocytosed cargo remains undefined. Methods We investigated the role of ALDOA using integrated approaches, including The Cancer Genome Atlas data analysis and in vitro assays of lung adenocarcinoma cell lines to evaluate macropinocytosis, lysosomal degradation, lysosomal pH, and interactions with V-ATPase. We also assessed mTORC1 signaling and cell proliferation under nutrient-deprived and anchorage-independent conditions. In vivo relevance was tested in xenograft tumor models. Results High expression of ALDOA correlated with a poor prognosis for patients with KRAS-mutant lung adenocarcinoma. Functionally, ALDOA selectively regulated lysosomal degradation of macropinocytosed proteins without affecting their uptake. Mechanistically, ALDOA interacted physically with V-ATPase subunits to increase lysosomal acidification, uncovering a novel, non-enzymatic role that is independent of its glycolytic function. This interaction was essential for efficient nutrient utilization, sustained mTORC1 activity, and cell proliferation under metabolic and mechanical stress. In vivo, depletion of ALDOA inhibited macropinocytosis-dependent tumor growth, phenocopying treatment with 5-(N-Ethyl-N-isopropyl) amiloride. Conclusion Our study identifies a novel, non-enzymatic function of ALDOA as a critical regulator of lysosomal degradation of macropinocytosed proteins via interaction with V-ATPase. This mechanism is essential for metabolic adaptation and growth of KRAS-mutant tumors under stress conditions. Targeting ALDOA offers a promising therapeutic strategy for cancers that rely on extracellular nutrient scavenging.

Metformin is one of the most widely used anti-diabetic agents in the world, and a growing body of evidence suggests that it may also be effective as an anti-cancer drug. Observational studies have shown that metformin reduces cancer incidence and cancer-related mortality in multiple types of cancer. These results have drawn attention to the mechanisms underlying metformins anti-cancer effects, which may include triggering of the AMP-activated protein kinase (AMPK) pathway, resulting in vulnerability to an energy crisis (leading to cell death under conditions of nutrient deprivation) and a reduction in circulating insulin/ IGF-1 levels. Clinical trials are currently underway to determine the benefits, appropriate dosage, and tolerability of metformin in the context of cancer therapy. This review highlights fundamental aspects of the molecular mechanisms underlying metformin’s anti-cancer effects, describes the epidemiological evidence and ongoing clinical challenges, and proposes directions for future translational research.