Gastric cancer adapts high lipid microenvironment via suppressing PPARG-FABP1 axis after arriving in the lymph node
Aim: Gastric cancer (GC) primarily metastasizes through lymphatic channels, although lymphatic metastasis remains relatively inefficient. Changes in cellular metabolism, known as metabolic reprogramming, plays a significant role in the adaptive survival of cells during the process. Therefore, unders...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725002721 |
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| author | Yinan Liu Liang Tang Baifu Peng Shaoji Zhao Ziling Shao Kaiyu Sun Jinning Ye Wei Chen Jianbo Xu |
| author_facet | Yinan Liu Liang Tang Baifu Peng Shaoji Zhao Ziling Shao Kaiyu Sun Jinning Ye Wei Chen Jianbo Xu |
| author_sort | Yinan Liu |
| collection | DOAJ |
| description | Aim: Gastric cancer (GC) primarily metastasizes through lymphatic channels, although lymphatic metastasis remains relatively inefficient. Changes in cellular metabolism, known as metabolic reprogramming, plays a significant role in the adaptive survival of cells during the process. Therefore, understanding the mechanism underlying metabolic reprogramming in lymph node (LN) metastasis is crucial for the development of targeted therapies for advanced gastric cancer. This study aimed to investigate the metabolic adaptations of GC cells during LN metastasis, with a particular focus on lipid metabolism reprogramming. Methods: Non-targeted lipidomic sequencing, combined with tumor cell flow sorting and RNA sequencing, was used to explore differences in lipid microenvironments and changes in lipid metabolism pathways between lymph nodes and primary tumors. Single-cell sequencing data were analyzed to confirm these results. Transmission electron microscopy, BODIPY 581/591 staining, and ferroptosis inhibitors were used to confirm the effects of arachidonic acid (AA) on ferroptosis sensitivity in gastric cancer. Public databases and ChIP-qPCR tests were used to investigate the role of PPARγ pathway in regulating FABP1 transcription. Results: Lipid metabolism pathway was inhibited following lymph node metastasis, with reduced lipid catabolites observed in the lymph nodes. Single-cell data also supported these findings. Physiological concentrations of AA were shown to increase ferroptosis sensitivity, lipid peroxidation, and mitochondrial damage in gastric cancer cells. FABP1 was significantly downregulated in lymph nodes, which mediated the uptake of AA, mitochondrial destruction, and lipid peroxidation. Further analysis revealed that PPARγ, a regulator of FABP1 transcription, was significantly downregulated after lymph node metastasis. Furthermore, our findings revealed that AA reduced the stability of PPARγ protein. Conclusion: The high concentration of AA in the lymph nodes microenvironment can increase the sensitivity of gastric cancer cells to ferroptosis. Mechanically, AA inhibits the PPARγ pathway to downregulate FABP1 expression, thereby suppressing AA uptake and preventing ferroptosis of gastric cancer cells. |
| format | Article |
| id | doaj-art-bb20ef19218f45dfb252f6498786d67e |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-bb20ef19218f45dfb252f6498786d67e2025-08-24T05:12:31ZengElsevierRedox Biology2213-23172025-09-018510375910.1016/j.redox.2025.103759Gastric cancer adapts high lipid microenvironment via suppressing PPARG-FABP1 axis after arriving in the lymph nodeYinan Liu0Liang Tang1Baifu Peng2Shaoji Zhao3Ziling Shao4Kaiyu Sun5Jinning Ye6Wei Chen7Jianbo Xu8Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of China; Department of General Surgery, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110000, Liaoning Province, People's Republic of ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of ChinaDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of China; Corresponding author.Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of China; Corresponding author.Aim: Gastric cancer (GC) primarily metastasizes through lymphatic channels, although lymphatic metastasis remains relatively inefficient. Changes in cellular metabolism, known as metabolic reprogramming, plays a significant role in the adaptive survival of cells during the process. Therefore, understanding the mechanism underlying metabolic reprogramming in lymph node (LN) metastasis is crucial for the development of targeted therapies for advanced gastric cancer. This study aimed to investigate the metabolic adaptations of GC cells during LN metastasis, with a particular focus on lipid metabolism reprogramming. Methods: Non-targeted lipidomic sequencing, combined with tumor cell flow sorting and RNA sequencing, was used to explore differences in lipid microenvironments and changes in lipid metabolism pathways between lymph nodes and primary tumors. Single-cell sequencing data were analyzed to confirm these results. Transmission electron microscopy, BODIPY 581/591 staining, and ferroptosis inhibitors were used to confirm the effects of arachidonic acid (AA) on ferroptosis sensitivity in gastric cancer. Public databases and ChIP-qPCR tests were used to investigate the role of PPARγ pathway in regulating FABP1 transcription. Results: Lipid metabolism pathway was inhibited following lymph node metastasis, with reduced lipid catabolites observed in the lymph nodes. Single-cell data also supported these findings. Physiological concentrations of AA were shown to increase ferroptosis sensitivity, lipid peroxidation, and mitochondrial damage in gastric cancer cells. FABP1 was significantly downregulated in lymph nodes, which mediated the uptake of AA, mitochondrial destruction, and lipid peroxidation. Further analysis revealed that PPARγ, a regulator of FABP1 transcription, was significantly downregulated after lymph node metastasis. Furthermore, our findings revealed that AA reduced the stability of PPARγ protein. Conclusion: The high concentration of AA in the lymph nodes microenvironment can increase the sensitivity of gastric cancer cells to ferroptosis. Mechanically, AA inhibits the PPARγ pathway to downregulate FABP1 expression, thereby suppressing AA uptake and preventing ferroptosis of gastric cancer cells.http://www.sciencedirect.com/science/article/pii/S2213231725002721Gastric cancerArachidonic acidFerroptosisLymphatic channels |
| spellingShingle | Yinan Liu Liang Tang Baifu Peng Shaoji Zhao Ziling Shao Kaiyu Sun Jinning Ye Wei Chen Jianbo Xu Gastric cancer adapts high lipid microenvironment via suppressing PPARG-FABP1 axis after arriving in the lymph node Redox Biology Gastric cancer Arachidonic acid Ferroptosis Lymphatic channels |
| title | Gastric cancer adapts high lipid microenvironment via suppressing PPARG-FABP1 axis after arriving in the lymph node |
| title_full | Gastric cancer adapts high lipid microenvironment via suppressing PPARG-FABP1 axis after arriving in the lymph node |
| title_fullStr | Gastric cancer adapts high lipid microenvironment via suppressing PPARG-FABP1 axis after arriving in the lymph node |
| title_full_unstemmed | Gastric cancer adapts high lipid microenvironment via suppressing PPARG-FABP1 axis after arriving in the lymph node |
| title_short | Gastric cancer adapts high lipid microenvironment via suppressing PPARG-FABP1 axis after arriving in the lymph node |
| title_sort | gastric cancer adapts high lipid microenvironment via suppressing pparg fabp1 axis after arriving in the lymph node |
| topic | Gastric cancer Arachidonic acid Ferroptosis Lymphatic channels |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725002721 |
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