2. Academic Validation
  3. MAL2 reprograms lipid metabolism in intrahepatic cholangiocarcinoma via EGFR/SREBP-1 pathway based on single-cell RNA sequencing

MAL2 reprograms lipid metabolism in intrahepatic cholangiocarcinoma via EGFR/SREBP-1 pathway based on single-cell RNA sequencing

  • Cell Death Dis. 2024 Jun 12;15(6):411. doi: 10.1038/s41419-024-06775-7.
Tian Huang # 1,  Hengsong Cao # 1,  Chuan Liu # 1,  Xiaohu Sun 1,  Shipeng Dai 1,  Li Liu 2,  Yuliang Wang 3,  Cheng Guo 4,  Xuehao Wang 5,  Yun Gao 6,  Weiwei Tang 7,  Yongxiang Xia 8
Affiliations

Affiliations

  • 1 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key laboratory of Hepatobiliary cancers,Nanjing, China, Nanjing, Jiangsu, China.
  • 2 State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
  • 3 School of Basic Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4 Department of Otorhinolaryngology Head and Neck Surgery, Guangzhou First People's Hospital, Guangzhou, Guangdong, China.
  • 5 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key laboratory of Hepatobiliary cancers,Nanjing, China, Nanjing, Jiangsu, China. wangxh@njmu.edu.cn.
  • 6 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key laboratory of Hepatobiliary cancers,Nanjing, China, Nanjing, Jiangsu, China. gaoyunjs@sina.com.
  • 7 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key laboratory of Hepatobiliary cancers,Nanjing, China, Nanjing, Jiangsu, China. 1243773473twww@sina.com.
  • 8 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key laboratory of Hepatobiliary cancers,Nanjing, China, Nanjing, Jiangsu, China. yx_xia@njmu.edu.cn.
  • # Contributed equally.
PMID: 38866777 DOI: 10.1038/s41419-024-06775-7
Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive Cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC Cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/Akt/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced Apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.

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