{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T02:19:20Z","timestamp":1784945960106,"version":"3.55.0"},"reference-count":78,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T00:00:00Z","timestamp":1703548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Cinnamic acid, ferulic acid, and the flavonoids quercetin and taxifolin (dihydroquercetin) are naturally occurring compounds found in plants. They are often referred to as polyphenols and are known, among others, for their pharmacological effects supporting health through the inhibition of aging processes and oxidative stress. To improve their bioavailability, pharmacological activities, and safety, the creation of novel flavonoid\u2013phenolic acid hybrids is an area of active research. Previous work showed that such hybridization products of phenolic acids and flavonoids enhanced the resilience of neuronal cells against oxidative stress in vitro, and attenuated cognitive impairment in a mouse model of Alzheimer\u2019s disease (AD) in vivo. Notably, the therapeutic effects of the hybrid compounds we obtained were more pronounced than the protective activities of the respective individual components. The underlying mechanisms mediated by the flavonoid\u2013phenolic acid hybrids, however, remained unclear and may differ from the signaling pathways activated by the originating structures of the respective individual phenolic acids or flavonoids. In this study, we characterized the effects of four previously described potent flavonoid\u2013phenolic acid hybrids in models of oxidative cell death through ferroptosis. Ferroptosis is a type of iron-dependent regulated cell death characterized by lipid peroxidation and mitochondrial ROS generation and has been linked to neurodegenerative conditions. In models of ferroptosis induced by erastin or RSL3, we analyzed mitochondrial (lipid) peroxidation, mitochondrial membrane integrity, and Ca2+ regulation. Our results demonstrate the strong protective effects of the hybrid compounds against ROS formation in the cytosol and mitochondria. Importantly, these protective effects against ferroptosis were not mediated by radical scavenging activities of the phenolic hybrid compounds but through inhibition of mitochondrial complex I activity and reduced mitochondrial respiration. Our data highlight the effects of flavonoid\u2013phenolic acid hybrids on mitochondrial metabolism and further important mitochondrial parameters that collectively determine the health and functionality of mitochondria with a high impact on the integrity and survival of the neuronal cells.<\/jats:p>","DOI":"10.3390\/antiox13010044","type":"journal-article","created":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T04:40:44Z","timestamp":1703565644000},"page":"44","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Flavonoid\u2013Phenolic Acid Hybrids Are Potent Inhibitors of Ferroptosis via Attenuation of Mitochondrial Impairment"],"prefix":"10.3390","volume":"13","author":[{"given":"Madeline","family":"G\u00fcnther","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Karl-von-Frisch-Str. 2, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samentha","family":"Dabare","sequence":"additional","affiliation":[{"name":"Marburg Center of Mind, Brain, and Behavior\u2014CMBB, Hans-Meerwein-Str. 6, 35032 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Marburg Center of Mind, Brain, and Behavior\u2014CMBB, Hans-Meerwein-Str. 6, 35032 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Gunesch","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6773-6245","authenticated-orcid":false,"given":"Michael","family":"Decker","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5121-5015","authenticated-orcid":false,"given":"Carsten","family":"Culmsee","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Karl-von-Frisch-Str. 2, 35043 Marburg, Germany"},{"name":"Marburg Center of Mind, Brain, and Behavior\u2014CMBB, Hans-Meerwein-Str. 6, 35032 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a risk factor for neurodegenerative disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. 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