2. Academic Validation
  3. 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

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

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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