2. Academic Validation
  3. Microbial riboflavin inhibits ceramide synthase 3 to lower ceramide (d18:1/26:0) and delay colorectal cancer progression

Microbial riboflavin inhibits ceramide synthase 3 to lower ceramide (d18:1/26:0) and delay colorectal cancer progression

  • Cell Metab. 2025 Sep 2;37(9):1852-1869.e8. doi: 10.1016/j.cmet.2025.06.002.
Ruize Qu 1,  Yi Zhang 2,  Bora Kim 3,  Guangyi Zeng 4,  Pengcheng Wang 5,  Weike Shaoyong 6,  Ying Huang 6,  Wanwan Guo 6,  Yang Chen 7,  Ping Wang 8,  Qing Yang 2,  Siyi Lu 2,  Xin Zhou 2,  Jing Weng 2,  Jinkun Xu 9,  Jun Lin 9,  Kai Wang 9,  Yanpeng Ma 2,  Shogo Takahashi 3,  Yuhong Luo 3,  Xiaoting Yu 3,  Kristopher W Krausz 3,  Yanli Pang 10,  Tianpei Hong 6,  Zhipeng Zhang 11,  Wei Fu 12,  Frank J Gonzalez 13,  Lulu Sun 14
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Cancer Center, Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Peking University Third Hospital, Beijing 100191, China; Department of General Surgery, Peking University Third Hospital, Beijing 100191, China.
  • 2 Department of General Surgery, Peking University Third Hospital, Beijing 100191, China.
  • 3 Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • 4 Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Cancer Center, Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Peking University Third Hospital, Beijing 100191, China; Center for Reproductive Medicine, Department of Obstetrics and Gynecology, State Key Laboratory of Female Fertility Preservation and Promotion, Peking University Third Hospital, Beijing 100191, China.
  • 5 Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China.
  • 6 Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Cancer Center, Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Peking University Third Hospital, Beijing 100191, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China.
  • 7 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
  • 8 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 9 Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China.
  • 10 Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China; Center for Reproductive Medicine, Department of Obstetrics and Gynecology, State Key Laboratory of Female Fertility Preservation and Promotion, Peking University Third Hospital, Beijing 100191, China.
  • 11 Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Cancer Center, Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Peking University Third Hospital, Beijing 100191, China; Department of General Surgery, Peking University Third Hospital, Beijing 100191, China. Electronic address: zhangzhipeng06@126.com.
  • 12 Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Cancer Center, Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Peking University Third Hospital, Beijing 100191, China; Department of General Surgery, Peking University Third Hospital, Beijing 100191, China. Electronic address: fuwei@bjmu.edu.cn.
  • 13 Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: gonzalef@mail.nih.gov.
  • 14 Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Cancer Center, Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Peking University Third Hospital, Beijing 100191, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China. Electronic address: lulusun@bjmu.edu.cn.
PMID: 40609532 DOI: 10.1016/j.cmet.2025.06.002
Abstract

Ceramide metabolism dysregulation links to colorectal Cancer (CRC) progression, yet the mechanism remains unknown. d18:1/26:0 ceramide (C26) levels were elevated in patients with CRC and mouse models, which activated epidermal growth factor receptor (EGFR) by binding its extracellular region to promote Cancer cell proliferation. The rise of C26 levels was mainly driven by heightened ceramide synthase 3 (CERS3) activity. High CERS3 expression generally accelerated tumor progression, yet some patients exhibited significant heterogeneity, suggesting endogenous metabolites available to affect CERS3 activity. We found that the abundance of Bacteroides cellulosilyticus affects tumor heterogeneity by producing riboflavin that inhibits CERS3 activity, thus delaying CRC progression. Moreover, aclidinium bromide, an FDA-approved drug, exhibited significant inhibitory effects on CERS3 activity, suggesting its potential application in CRC treatment. These findings elucidate the metabolic pathways and mechanisms underlying ceramide's impact on CRC, highlighting that targeting CERS3 inhibition represents a promising therapeutic strategy for CRC.

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