{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T09:00:03Z","timestamp":1766998803916,"version":"3.48.0"},"reference-count":83,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T00:00:00Z","timestamp":1766793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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 \u03bcM and 3.764 \u03bcM 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 \u201cmetabolism &amp; metal homeostasis\u201d 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.<\/jats:p>","DOI":"10.3390\/cancers18010092","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T08:47:27Z","timestamp":1766998047000},"page":"92","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["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"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4421-6818","authenticated-orcid":false,"given":"Hao","family":"Dong","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7403-7410","authenticated-orcid":false,"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongyue","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenjie","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9516-1466","authenticated-orcid":false,"given":"Xinyue","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiyunyi","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulin","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiacheng","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiwei","family":"Diao","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2933-8715","authenticated-orcid":false,"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7774-1577","authenticated-orcid":false,"given":"Ruixin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9398-3308","authenticated-orcid":false,"given":"Dayang","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weijia","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, 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