Qu Ruize, Zhang Yi, Kim Bora, Zeng Guangyi, Wang Pengcheng, Shaoyong Weike, Huang Ying, Guo Wanwan, Chen Yang, Wang Ping, Yang Qing, Lu Siyi, Zhou Xin, Weng Jing, Xu Jinkun, Lin Jun, Wang Kai, Ma Yanpeng, Takahashi Shogo, Luo Yuhong, Yu Xiaoting, Krausz Kristopher W, Pang Yanli, Hong Tianpei, Zhang Zhipeng, Fu Wei, Gonzalez Frank J, Sun Lulu
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.
Department of General Surgery, Peking University Third Hospital, Beijing 100191, China.
Cell Metab. 2025 Jun 26. doi: 10.1016/j.cmet.2025.06.002.
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.
神经酰胺代谢失调与结直肠癌（CRC）进展相关，但具体机制尚不清楚。在CRC患者和小鼠模型中，d18:1/26:0神经酰胺（C26）水平升高，其通过结合表皮生长因子受体（EGFR）的细胞外区域来激活EGFR，从而促进癌细胞增殖。C26水平的升高主要由神经酰胺合成酶3（CERS3）活性增强驱动。高CERS3表达通常会加速肿瘤进展，但一些患者表现出显著的异质性，提示存在可影响CERS3活性的内源性代谢物。我们发现，解纤维梭菌的丰度通过产生抑制CERS3活性的核黄素来影响肿瘤异质性，从而延缓CRC进展。此外，美国食品药品监督管理局（FDA）批准的药物阿地溴铵对CERS3活性具有显著抑制作用，提示其在CRC治疗中的潜在应用价值。这些发现阐明了神经酰胺影响CRC的代谢途径和机制，强调靶向抑制CERS3是一种有前景的CRC治疗策略。
