S100P is a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 8, 2025

Ferroptosis is a newly identified programmed cell death induced by iron-driven lipid peroxidation and implicated as potential approach for tumor treatment. However, emerging evidence indicates that hepatocellular carcinoma (HCC) cells are generally resistant to ferroptosis the underlying molecular mechanism poorly understood. Here, our study confirms S100 calcium binding protein P (S100P), which significantly up-regulated in ferroptosis-resistant HCC cells, efficiently inhibits ferroptosis. Mechanistically, S100P facilitates lysosomal degradation of acetyl-CoA carboxylase alpha (ACC1), indispensable de novo biosynthesis lipids. Loss elevates expression ACC1 promotes ferroptotic sensitivity cells. S100P-mediated relies on RAB5C, directs lysosome via P62-dependent selective autophagy. Knockdown RAB5C or P62 abrogates S100P-induced restores resistance Our work reveals an alternative anti-ferroptosis pathway suggests promising druggable target ferroptosis-related therapy HCC. Resistance remains be authors identify (S100P) suppressor (ACC1) downregulate biosynthesis.

Language: Английский

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Sorafenib enhanced the function of myeloid-derived suppressor cells in hepatocellular carcinoma by facilitating PPARα-mediated fatty acid oxidation

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 28, 2025

Sorafenib, an FDA-approved drug for advanced hepatocellular carcinoma (HCC), faces resistance issues, partly due to myeloid-derived suppressor cells (MDSCs) that enhance immunosuppression in the tumor microenvironment (TME). Various murine HCC cell lines and MDSCs were used a series of vitro vivo experiments. These included subcutaneous models, viability assays, flow cytometry, immunohistochemistry, RNA sequencing. analyzed chemotaxis, immunosuppressive functions, fatty acid oxidation (FAO), PPARα expression. The impact sorafenib on growth, MDSC infiltration, differentiation, function was assessed, alongside modulation these processes by PPARα. Here, we revealed increased infiltration enhanced TME after treatment with sorafenib. Moreover, our results indicated induced accumulation mediated CCR2, pharmacological blockade CCR2 markedly reduced migration growth. Mechanistically, promoted effect uptake ability modulated peroxisome proliferator-activated receptor α (PPARα)-mediated (FAO). In addition, tumor-bearing mice fed high-fat diet (HFD) at beginning administration had worse outcomes than regular diet. Genetic deficiency weakens HCC. Pharmacological inhibition has synergistic anti-tumor sorafenib, which is attenuated MDSCs. significantly inhibited differentiation macrophages upregulating expression suppressing PU.1-CSF1R pathway. Overall, study demonstrated facilitating PPARα-mediated FAO further augmenting resistance, sheds light dietary management improves therapeutic response

Language: Английский

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GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 5, 2025

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Abnormally high expression Golgi protein 73 (GP73) and pyruvate kinase M2 (PKM2) intimately associated with HCC progression. However, as secreted proteins, role their extracellular secretions in progression remains unclear. Here, we demonstrated that GP73 was positively correlated PKM2. interacted PKM2 to promote SUMO1 modification PKM2, which turn enhanced interaction This process continuously promoted transfer from cytoplasm membrane cells, finally secretion. Extracellular synergistically angiogenesis polarization M2-type macrophages, thereby leading sorafenib resistance HCC. Sorafenib combined shikonin, a specific inhibitor has strong anti-tumor effect. study reveals enhancing secretion promoting progression, providing theoretical basis drug targets for therapy.

Language: Английский

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SCARA5 deficiency inhibits ferroptosis via regulating iron homeostasis and results in sorafenib resistance in hepatocellular carcinoma

Cellular Signalling, Journal Year: 2025, Volume and Issue: unknown, P. 111656 - 111656

Published: Feb. 1, 2025

Language: Английский

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Circular RNAs: characteristics, biogenesis, mechanisms and functions in liver cancer

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: Aug. 30, 2021

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignancies globally. Despite aggressive and multimodal treatment regimens, overall survival HCC patients remains poor. Main Circular RNAs (circRNAs) are noncoding (ncRNAs) with covalently closed structures tissue- or organ-specific expression patterns in eukaryotes. They highly stable have important biological functions, including acting as microRNA sponges, protein scaffolds, transcription regulators, translation templates interacting RNA-binding protein. Recent advances indicated that circRNAs present abnormal tissues their dysregulation contributes to initiation progression. Furthermore, researchers revealed some might serve diagnostic biomarkers drug targets clinical settings. In this review, we systematically evaluate characteristics, biogenesis, mechanisms functions further discuss current shortcomings potential directions prospective studies on liver cancer-related circRNAs. Conclusion CircRNAs a novel class ncRNAs play significant role progression, but internal applications need investigation.

Language: Английский

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