A CD147-targeted small-molecule inhibitor potentiates gemcitabine efficacy by triggering ferroptosis in pancreatic ductal adenocarcinoma
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.
Authors
- Jun Yu (ORCID: https://orcid.org/0000-0001-5009-2941)
- Chongbiao Huang (ORCID: https://orcid.org/0000-0001-9468-9168)
- Song Gao (ORCID: https://orcid.org/0000-0001-7427-6681)
- Tiansuo Zhao (ORCID: https://orcid.org/0000-0003-1631-6299)
- C Ma (ORCID: https://orcid.org/0000-0001-5236-8374)
- Yukuan Feng (ORCID: https://orcid.org/0009-0005-6497-0748)
- Jingyuan Xu (ORCID: https://orcid.org/0000-0003-0352-9930)
- Weihua Guo (ORCID: https://orcid.org/0000-0002-5839-7114)
- Xiuchao Wang (ORCID: https://orcid.org/0000-0002-3205-8544)
- Jiaqi Li (ORCID: https://orcid.org/0009-0005-5564-6241)
- Bowen Ding
- Antao Chang (ORCID: https://orcid.org/0000-0001-9442-619X)
- Pengyu Wang (ORCID: https://orcid.org/0000-0002-6336-7673)
- Zhe Li (ORCID: https://orcid.org/0000-0002-6392-7837)
- Hongwei Wang (ORCID: https://orcid.org/0000-0003-3581-8892)
- Yifei Wang (ORCID: https://orcid.org/0000-0002-2073-2837)
- Yuan‐Han Yang (ORCID: https://orcid.org/0000-0002-1918-9021)
- Pei Cao (ORCID: https://orcid.org/0000-0002-4240-5124)
- Liang Zhao (ORCID: https://orcid.org/0000-0001-8958-074X)
- Jihui Hao (ORCID: https://orcid.org/0000-0002-5598-6706)
- Shouyi Li
- Fengyi Yin
- Tianxing Zhou (ORCID: https://orcid.org/0009-0006-0150-1343)
Institutions
- Tianjin Medical University Cancer Institute and Hospital (CN)
- Tianjin Medical University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102292
- Citations
- 5
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Tianjin Municipal Health Commission
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- China Postdoctoral Science Foundation
- Natural Science Foundation of Tianjin City
- Science and Technology Department, Heilongjiang Province
- Tianjin Science and Technology Program