TL;DR
It is proposed SLC25A1 is associated with metabolic reprogramming in HCC and contribute to tumor progression by promoting lipogenesis and offering a promising therapeutic target for early intervention and treatment.
Hepatocellular carcinoma (HCC) poses a significant global health burden with limited therapeutic options, particularly for non-viral etiologies. The mitochondrial solute carrier SLC25A43 is implicated in cellular redox homeostasis, yet its role in HCC remains unclear. This study aimed to comprehensively investigate the expression pattern, clinical significance, biological function, and potential mechanisms of SLC25A43 in HCC. Utilizing multi-omics data from public databases (TCGA-LIHC, GEO, and HPA), we performed integrated bioinformatic analyses. SLC25A43 was consistently upregulated in HCC tissues compared with non-tumorous liver tissues and demonstrated strong diagnostic value (AUC = 0.861). High SLC25A43 expression was significantly associated with advanced tumor stage, metastasis, and adverse clinicopathological features. Survival analyses identified SLC25A43 as an independent prognostic risk factor for overall survival, progression-free interval, and disease-specific survival. Functional enrichment analyses suggested that SLC25A43 is involved in mitochondrial oxidative phosphorylation, energy metabolism, and immune-related pathways. Immune infiltration analyses using ssGSEA, xCell, and TIMER consistently revealed negative correlations between SLC25A43 expression and multiple antitumor immune cell populations, particularly CD8 + T cells. Experimental validation confirmed that SLC25A43 was significantly upregulated in HCC tissues at both mRNA and protein levels. Functional assays in Huh-7, Hep-LM3, MHCC97H, and LO2 cells demonstrated that SLC25A43 knockdown inhibited, whereas overexpression promoted, cell proliferation and migration. Rescue experiments further verified the specificity of these effects. Mechanistically, SLC25A43 regulated intracellular ATP production, ROS accumulation, and glutathione metabolism, indicating a role in redox homeostasis and energy metabolism. In addition, PBMC co-culture experiments showed that SLC25A43 suppressed CD8 + T-cell cytotoxic activity by reducing Granzyme B expression. A prognostic nomogram incorporating SLC25A43 exhibited favorable predictive performance and was successfully validated in two independent GEO cohorts. SLC25A43 is a novel diagnostic and prognostic biomarker for HCC. Its upregulation promotes tumor progression through metabolic reprogramming, redox homeostasis remodeling, and suppression of antitumor immune responses. These findings highlight SLC25A43 as a promising therapeutic target and provide new insights into the metabolic-immune regulatory network in hepatocellular carcinoma.
Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. The molecular alterations in tumors that promote metabolic diversity and distinct targetable dependencies remain poorly defined. The mitochondrial transporter SLC25A20, also known as carnitine-acylcarnitine translocase (CACT), is crucial for fatty acid β-oxidation (FAO) by importing acylcarnitines into the mitochondrial matrix. Here, we demonstrate that SLC25A20 is significantly upregulated in lung adenocarcinoma (LUAD) tissues and cells, and its expression correlates with poor patient survival. Gain- and loss-of-function experiments reveal that SLC25A20 promotes tumor cell proliferation, survival, migration, and invasion by enhancing FAO-associated mitochondrial bioenergetics and suppressing apoptosis. Mechanistically, SLC25A20-mediated FAO maintains mitochondrial function and supports oxidative phosphorylation (OXPHOS), thereby sustaining tumor bioenergetics and redox homeostasis. Pharmacological inhibition or genetic silencing of SLC25A20 impairs tumor growth in vivo. These findings establish SLC25A20 as a key metabolic driver in LUAD and suggest it may be a therapeutic target.
High MCT4 expression in TAMs may be associated with metabolic reprogramming toward glycolysis, and could promote M2 polarization of TAMs, thereby contributing to HCC progression and poor clinical outcomes.
Abstract Background Hepatocellular carcinoma (HCC) is characterized by pronounced metabolic reprogramming and is frequently accompanied by the development of an immunosuppressive microenvironment. However, the key molecular mediators linking tumour metabolic dysregulation to immune microenvironment remodelling remain insufficiently defined. This study aimed to identify critical metabolic genes in HCC and to investigate their roles in lipid metabolic reprogramming and immunosuppression. Methods A deep autoencoder was used to extract latent metabolic features from HCC and identify TALDO1 as a key candidate gene. The expression pattern and prognostic significance of TALDO1 were evaluated across multiple independent cohorts and further validated in clinical specimens. Multi‐omics analyses combined with experimental validation were then used to elucidate the role of TALDO1 in lipid metabolic reprogramming and its effects on immune microenvironment remodelling in HCC. Results TALDO1 was identified as a key metabolic gene associated with HCC progression and was consistently upregulated across multiple clinical cohorts. Mechanistically, TALDO1 promoted lipogenesis and lipid accumulation in HCC cells by suppressing AMPK activation and sustaining SREBP1 maturation. TALDO1 silencing also reduced the secretion of several fatty acids and lipid mediators. Multi‐omics analyses together with multiplex immunofluorescence validation showed that high TALDO1 expression was associated with an immunosuppressive microenvironment in HCC. Coculture experiments further demonstrated that TALDO1 silencing attenuated the ability of HCC cells to induce M2‐like macrophage polarization and promote phenotypes associated with T‐cell exhaustion. In vivo, TALDO1 loss was accompanied by reduced immunosuppressive cell infiltration, enhanced effector T‐cell activity, and impaired tumour growth. Consistently, TALDO1 silencing also markedly suppressed tumour growth in patient‐derived xenograft models. Conclusions TALDO1 promotes lipid metabolic reprogramming in HCC and participates in the formation of an immunosuppressive microenvironment. These findings suggest that TALDO1 may serve as a key molecule linking metabolic abnormalities to immune microenvironment remodelling and may have potential therapeutic significance. Key points TALDO1 promotes lipid metabolic reprogramming in HCC by regulating AMPK/SREBP1 signaling. TALDO1 is associated with the formation of an immunosuppressive tumour microenvironment. Multi‐omics analyses identified an association of TALDO1 with HCC progression and poor prognosis.
Hepatocellular carcinoma and cholangiocarcinoma, the most common primary liver cancers, are usually considered quite different pathologies. However, convergent metabolic reprogramming across different progenitor cells can result in similar molecular alterations and, even in a combined form of cancer that is characterized by transitional features and a shared phenotype. In this review, we summarize essential steps in glucose and lipid metabolism to distinguish similarities in glucose and energy metabolism reprogramming from divergent lipid remodeling in different types of primary liver cancers. We show the convergent nature of metabolic alterations in glucose decomposition and related mitochondrial enzymes. Also, we outline the essential role of lactate in promoting cell viability, adaptation to increased biomass synthesis, and fueling surrounding cancer cells to support their growth and proliferation. Lipid metabolism, in contrast, was found to be dramatically different between primary liver cancers. Hepatocellular carcinoma relies on de novo fatty acids synthesis, for which mitochondrial activity shifts from energy production to citrate efflux. Cholangiocarcinoma, in contrast, relies on fatty acids uptake from the extracellular space and, at later stages, even engages in beta-oxidation, which is uncharacteristic of hepatocellular carcinoma. This yields an altered lipid portrait for these pathologies despite the overall convergent alterations in energy metabolism. With this review, we provide not only fundamental insights for further primary liver tumor metabolism investigation, but also an emphasis on the independence of lipid alterations from energy metabolism reprogramming, vital for further basic and translational applications of metabolomics and lipidomics to a broad range of cancers.
Functional enrichment analysis reveals that SLC25A39 is commonly associated with immune-related pathways and cell cycle-related pathways in the pan-cancer dataset.