Li Jiaqi, Ma Chaozhe, Cao Pei, Guo Weihua, Wang Pengyu, Yang Yang, Ding Bowen, Yin Fengyi, Li Zhe, Wang Yifei, Li Shouyi, Huang Chongbiao, Wang Xiuchao, Zhou Tianxing, Chang Antao, Zhao Liang, Gao Song, Zhao Tiansuo, Wang Hongwei, Yu Jun, Xu Jingyuan, Feng Yukuan, Hao Jihui
Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Medical School of Nankai University, Tianjin 300070, China.
Cell Rep Med. 2025 Aug 19;6(8):102292. doi: 10.1016/j.xcrm.2025.102292.
CD147 has emerged as a promising tumor-specific therapeutic target. Identifying small-molecule inhibitors that promote its proteolysis represents a critical step toward advancing clinical translation, while elucidating its mechanisms of action could further accelerate this process. In this study, we identify dracorhodin perchlorate (DP) as a potent CD147 inhibitor that induces autophagy-dependent degradation. DP significantly inhibits cell proliferation and enhances sensitivity to gemcitabine in pancreatic cancer cells. Mechanistically, CD147 inhibition upregulates acyl-CoA synthetase long-chain family member 4 (ACSL4) expression through H3K9 lactylation and suppresses the sterol regulatory element-binding protein 1 (SREBP1)/stearoyl-CoA desaturase-1 (SCD1) signaling pathway, collectively disrupting the balance of polyunsaturated and monounsaturated fatty acids, ultimately triggering ferroptosis. The combination of DP and gemcitabine demonstrates remarkable synergistic anti-tumor effects in orthotopic xenograft models, spontaneous KPC mouse models, and patient-derived organoid (PDO) and xenograft (PDX) models. In conclusion, this study reveals a mechanism by which CD147 regulates ferroptosis and supports combining DP with gemcitabine as a therapeutic strategy to improve patient outcomes in pancreatic ductal adenocarcinoma.
CD147已成为一个有前景的肿瘤特异性治疗靶点。鉴定促进其蛋白水解的小分子抑制剂是推进临床转化的关键一步，而阐明其作用机制可进一步加速这一进程。在本研究中，我们鉴定出高氯酸血竭红素（DP）是一种有效的CD147抑制剂，可诱导自噬依赖性降解。DP显著抑制胰腺癌细胞的增殖并增强其对吉西他滨的敏感性。机制上，CD147抑制通过H3K9乳酸化上调酰基辅酶A合成酶长链家族成员4（ACSL4）的表达，并抑制固醇调节元件结合蛋白1（SREBP1）/硬脂酰辅酶A去饱和酶-1（SCD1）信号通路，共同破坏多不饱和脂肪酸和单不饱和脂肪酸的平衡，最终引发铁死亡。在原位异种移植模型、自发KPC小鼠模型以及患者来源的类器官（PDO）和异种移植（PDX）模型中，DP与吉西他滨联合显示出显著的协同抗肿瘤作用。总之，本研究揭示了CD147调节铁死亡的机制，并支持将DP与吉西他滨联合作为一种治疗策略，以改善胰腺导管腺癌患者的预后。
