Silibinin inhibits ethanol- or acetaldehyde-induced ferroptosis in liver cell lines

• Published in: Toxicology in Vitro Vol. 82; p. 105388
• Main Authors: Song, Xiao-Yu, Liu, Peng-Cheng, Liu, Wei-Wei, Zhou, Jia, Hayashi, Toshihiko, Mizuno, Kazunori, Hattori, Shunji, Fujisaki, Hitomi, Ikejima, Takashi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2022; Elsevier BV; Elsevier Science Ltd
• Subjects: Acetaldehyde; Autophagy; Cell Line; Cell lines; Degradation; Ethanol; Ferritin; Ferritins; Ferroptosis; Flavone glycosides; Flavonoids; Hepatocytes; Humans; Injury prevention; Iron; Liver; Liver cells; Liver diseases; Oxidative stress; Parkin protein; Protein Kinases; PTEN-induced putative kinase; Reactive Oxygen Species; Silibinin; Silybin; Ubiquitin-Protein Ligases; Ethanol; NCOA4; Ferroptosis; Nec-1; MDA; Autophagy; MDC; CQ; Acetaldehyde; PINK1; Alde; Sili; Silibinin; TFR1; FTH1; ROS; Eth; ALD; 3-MA; Liver cells; Fer-1; GSH
• ISSN: 0887-2333; 1879-3177; 1879-3177
• DOI: 10.1016/j.tiv.2022.105388

Alcoholic liver disease has become one of the main causes of liver injury, and its prevention and cure are important medical tasks. Silibinin, a natural flavonoid glycoside, is a conventional hepatic protectant. This study elucidates the modulation of ferroptosis in silibinin's protective effects on ethanol- or acetaldehyde-induced liver cell damage by using human carcinomatous liver HepG2 cells and immortalized liver HL7702 cells. Our results show that ferroptosis is induced in the cells treated with ethanol or acetaldehyde, as evidenced by the increased ROS stress and iron level. Silibinin resolves the oxidative stress and reduces iron level. Ferroptosis induced by ethanol- or acetaldehyde involving nuclear receptor co-activator 4 (NCOA4)-dependent autophagic degradation of ferritin, a protein for storing iron is rescued by silibinin. PINK1 and Parkin-mediated mitophagy is arrested in ethanol- or acetaldehyde-treated cells but reversed by silibinin. Ferritin degradation and ROS level are further increased when PINK1 or Parkin is silenced in the cells treated with ethanol or acetaldehyde. Collectively, our study reveals that silibinin inhibits ethanol- or acetaldehyde-induced ferroptosis in two liver cell lines, HepG2 and HL7702 cells, providing new therapeutic strategies for alcoholic liver injury. [Display omitted] •Ethanol or acetaldehyde triggers ferroptosis in hepatocytes.•Autophagy is involved in ferroptosis treated with ethanol or acetaldehyde.•Ethanol or acetaldehyde reduces PINK1/Parkin-mediated mitophagy in ferroptosis.•Silibinin inhibits ethanol- or acetaldehyde-induced ferroptosis in two liver cell lines.•Silibinin enhances mitophagy in ethanol- or acetaldehyde-induced liver injury.