2. Academic Validation
  3. ROS-mediated senescence and autophagy inhibition drive 5-FU/Aumolertinib synergy in colorectal cancer

ROS-mediated senescence and autophagy inhibition drive 5-FU/Aumolertinib synergy in colorectal cancer

  • Eur J Pharmacol. 2026 Jan 12:1011:178448. doi: 10.1016/j.ejphar.2025.178448.
Peipei Liu 1,  Xiao Wu 2,  Zuojie Jiang 3,  Pei Zhang 4,  Zixuan Meng 3,  Chenming Xu 3,  Di Ao 5,  Jing Jiang 6,  Hao Liu 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Bengbu Medical University, Bengbu, China; Department of Pediatrics, First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
  • 2 Chemotherapy Department of the First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
  • 3 School of Pharmacy, Bengbu Medical University, Bengbu, China.
  • 4 School of Pharmacy, Bengbu Medical University, Bengbu, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China.
  • 5 Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
  • 6 Emergency Surgery Department of the First Affiliated Hospital of Bengbu Medical University, Bengbu, China. Electronic address: [email protected].
  • 7 School of Pharmacy, Bengbu Medical University, Bengbu, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China. Electronic address: [email protected].
PMID: 41352706 DOI: 10.1016/j.ejphar.2025.178448
Abstract

Epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal Cancer (CRC) and promotes tumor invasion and metastasis. Although 5-fluorouracil (5-FU) serves as a first-line CRC therapeutic, its clinical utility is constrained by dose-dependent toxicity. This study demonstrated that combining 5-FU with the EGFR Inhibitor aumolertinib (AUM) synergistically suppressed CRC progression while reducing effective 5-FU doses. Transcriptomic and functional analyses linked this synergy to cellular senescence and autophagic flux blockade. Mechanistically, Reactive Oxygen Species (ROS) accumulation drives senescence and Autophagy inhibition, which inactivates the PI3K/Akt/mTOR pathway, thereby inhibiting CRC cell proliferation, invasion, and migration. Notably, ROS scavenging with N-acetylcysteine reversed these effects. The synergistic tumor growth inhibition was confirmed in HCT116 xenografts using low-dose combination therapy (5-FU 15 mg/kg + AUM 10 mg/kg). Collectively, these findings establish an ROS-dependent autophagic senescence axis as the molecular basis for 5-FU/AUM synergy, offering a novel strategic approach for CRC treatment.

Keywords

5-Fluorouracil; Aumolertinib; Autophagy-senescence axis; Colorectal cancer; Synergistic effect.

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