2. Academic Validation
  3. Tetrahydrobenzofuro[3,2-b]quinoline: A dual-acting autophagy-dependent DHODH inhibitor that provokes ferroptosis in lung cancer cells

Tetrahydrobenzofuro[3,2-b]quinoline: A dual-acting autophagy-dependent DHODH inhibitor that provokes ferroptosis in lung cancer cells

  • Bioorg Chem. 2025 Dec:167:109203. doi: 10.1016/j.bioorg.2025.109203.
Chong-Yu Liu 1,  Xue-Chang Gao 1,  Yan Ren 1,  Zhi-Yong Zhang 2,  Wan-Yun Huang 3
Affiliations

Affiliations

  • 1 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, China; Key Laboratory of Ecology of Rare and Endangered Species and Environmental Protection (Guangxi Normal University), Ministry of Education, Guilin 541006, China.
  • 2 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, China; Key Laboratory of Ecology of Rare and Endangered Species and Environmental Protection (Guangxi Normal University), Ministry of Education, Guilin 541006, China. Electronic address: [email protected].
  • 3 Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, College of Pharmacy, Guilin Medical University, 1 Zhi Yuan Road, Guilin 541199, China. Electronic address: [email protected].
PMID: 41205474 DOI: 10.1016/j.bioorg.2025.109203
Abstract

Autophagy-dependent ferroptosis-characterized by its unique metabolic regulatory mechanisms and tumor-selective cytotoxicity-has emerged as a promising therapeutic strategy for lung Cancer. In this study, we conducted mechanistic investigations on a series of tetrahydroquinoline-fused heterocycles designed via a pseudo-natural products (PNPs) strategy, as previously reported by our group. Among the tetrahydrobenzofuro[3,2-b]quinolines, the key compound 3af demonstrated potent anti-proliferative activity against lung Cancer cells (A549), with minimal cytotoxic effects on normal cells. Further mechanistic investigations revealed that 3af induced Ferroptosis through mitochondrial dysfunction, lipid peroxidation, and excessive accumulation of Reactive Oxygen Species. Moreover, western blotting and rescue experiments confirmed that 3af promoted the degradation of Dihydroorotate Dehydrogenase via an autophagy-dependent pathway, thereby elucidating a molecular crosstalk mechanism between Autophagy and Ferroptosis. In a murine xenograft tumor model, compound 3af exhibited significant antitumor efficacy at a dose of 20 mg/kg. It achieved a tumor inhibition rate of 58.33 %, with no notable toxicity observed in the treated Animals. These findings support the potential of PNP-based compounds as novel therapeutic agents targeting the autophagy-ferroptosis signaling axis in lung Cancer.

Keywords

Autophagy-dependent ferroptosis; Dihydroorotate dehydrogenase; Lung cancer cell lines; Tetrahydrobenzofuro[3,2-b]quinoline.

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