Baicalein mitigates anti-tuberculosis-induced liver injury via inhibition of lipid peroxidation mediated by ferritinophagy and ferroptosis: Involvement of Yap 1/NCOA4 signaling.
Source: PubMed, NCBI / U.S. National Library of Medicine
Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a leading cause of impaired anti-TB treatment efficacy in patients with tuberculosis. Baicalein (Bai), a dietary flavonoid from the root of Scutellaria baicalensis, exhibits diverse therapeutic effects across a broad spectrum of diseases. This study aimed to investigate the protective effects of Bai against ATB-DILI and to elucidate the role of ferritinophagy, using an integrated approach combining network pharmacology, animal models, and cellular assays. Bai treatment ameliorated ATB-DILI and hepatocyte injury in vivo and in vitro, respectively. Reactive oxygen species production, lipid accumulation, and cellular ferroptosis caused by anti-TB drugs were ameliorated following Bai treatment both in vivo and in vitro. Furthermore, Bai treatment alleviated excessive ferritinophagy induced by anti-TB drugs by modulating the nuclear receptor coactivator 4 (NCOA4)/ferritin heavy chain 1 (FTH1) signaling pathway. Notably, knockdown of YES-associated protein 1 (YAP1) abrogated the protective effects of Bai treatment, preventing it from alleviating the anti-TB drug-induced increase in NCOA4 expression, decrease in FTH1 expression, iron overload, and subsequent ferroptosis and lipid peroxidation in rat liver and hepatocytes. This study suggested that Bai treatment attenuates anti-TB drug-induced hepatocyte injury via inhibition of ferritinophagy activation-induced ferroptosis, which is regulated through the YAP1/NCOA4/FTH1 signa
Abstract
Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a leading cause of impaired anti-TB treatment efficacy in patients with tuberculosis. Baicalein (Bai), a dietary flavonoid from the root of Scutellaria baicalensis, exhibits diverse therapeutic effects across a broad spectrum of diseases. This study aimed to investigate the protective effects of Bai against ATB-DILI and to elucidate the role of ferritinophagy, using an integrated approach combining network pharmacology, animal models, and cellular assays. Bai treatment ameliorated ATB-DILI and hepatocyte injury in vivo and in vitro, respectively. Reactive oxygen species production, lipid accumulation, and cellular ferroptosis caused by anti-TB drugs were ameliorated following Bai treatment both in vivo and in vitro. Furthermore, Bai treatment alleviated excessive ferritinophagy induced by anti-TB drugs by modulating the nuclear receptor coactivator 4 (NCOA4)/ferritin heavy chain 1 (FTH1) signaling pathway. Notably, knockdown of YES-associated protein 1 (YAP1) abrogated the protective effects of Bai treatment, preventing it from alleviating the anti-TB drug-induced increase in NCOA4 expression, decrease in FTH1 expression, iron overload, and subsequent ferroptosis and lipid peroxidation in rat liver and hepatocytes. This study suggested that Bai treatment attenuates anti-TB drug-induced hepatocyte injury via inhibition of ferritinophagy activation-induced ferroptosis, which is regulated through the YAP1/NCOA4/FTH1 signaling pathway. These findings establish a novel therapeutic target for Bai in the treatment of ATB-DILI and provide a rational basis for its clinical application.