Synthesis and Biological Evaluation of a Caffeic Acid Phenethyl Ester Derivatives as Anti-Hepatocellular Carcinoma Agents via Inhibition of Mitochondrial Respiration and Disruption of Cellular Metabolism

  • Cancers (Basel). 2025 Dec 27;18(1):92. doi: 10.3390/cancers18010092.
Hao Dong  1 ,  Yuan Gao  1 ,  Dongyue Jiang  1 ,  Chenjie Feng  1 ,  Xinyue Gu  2 ,  Xiyunyi Cai  3 ,  Yulin Liu  1 ,  Guangyu Zhang  4 ,  Jiacheng Wen  4 ,  Weiwei Diao  5 ,  Ying Zhou  5 ,  Ruixin Li  1 ,  Dayang Xu  1 ,  Weijia Xie  4 ,  Liang Wu  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA.
  • 3. School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
  • 4. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 5. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
PMID: 41514605 DOI: 10.3390/cancers18010092
Abstract

Background: In this study, 28 caffeic acid phenethyl ester (CAPE) derivatives were designed and synthesized, and their anti-proliferative activities were evaluated against two representative human hepatocellular carcinoma (HCC) cell lines. The half-maximal inhibitory concentration (IC50) was used as the activity metric. Among these derivatives, compound WX006 displayed the most potent anti-proliferative effect, with IC50 values of 3.332 μM and 3.764 μM after 48 h of treatment, significantly lower than those of the parent compound CAPE. Consequently, WX006 was selected for further investigation into its antitumor efficacy and underlying mechanisms.

Methods: To investigate the pharmacological mechanism of WX006, we employed a combination of high-throughput transcriptomics, metabolomics, and mitochondrial function analysis to elucidate its intracellular mechanisms of action.

Results: WX006 disrupts cytoplasmic-mitochondrial metal ion homeostasis, triggering Ferroptosis and Cuproptosis through iron-copper dysregulation. Computational modeling revealed that WX006 selectively inhibits mitochondrial NDUFS2 subunit of respiratory chain complex I, which may induce NAD+ exhaustion and consequent Energy Metabolism collapse in tumor cells. These "metabolism & metal homeostasis" dual mechanisms collectively underpin its robust anti-tumor effects. Therapeutic efficacy of WX006 was further validated in murine H22 ectopic xenograft and Hepa1-6-Luc orthotopic xenograft models, where WX006 exhibited superior tumor suppression compared to sorafenib, alongside favorable safety profiles.

Conclusions: Our findings establish a foundational rationale for further pharmaceutical development of CAPE derivates as a promising therapeutic candidate for hepatocellular carcinoma.

Keywords
NAD+; NDUFS2; energy metabolism; ferroptosis; hepatocellular carcinoma; mitochondrial.
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