Gigantol Ameliorates Metabolic Dysfunction-Associated Steatohepatitis by Promoting TFEB-Mediated Lipophagy and Fatty Acid Oxidation

Gigantol, a naturally active molecule derived from the edible plant <i>Dendrobium</i>, has been demonstrated to have hepatoprotective potential, but its effect in the treatment of metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. Here, we found that gigantol treatment greatly corrected dyslipidemia, hepatic dysfunction, and hepatic histological changes that arrested MASH occurrence in high-fat and high-fructose-diet (HFFD)-fed mice. Mechanistically, gigantol promoted the nuclear translocation of the transcription factor EB (TFEB) to regulate the key factors of lipophagy and fatty acid oxidation to maintain hepatic lipid metabolism homeostasis. Consistent results were observed in palmitic acid-induced cell models. Notably, silencing TFEB reversed the effect of gigantol in enhancing lipophagy and fatty acid oxidation in vivo and in vitro. In summary, this study provides strong evidence to demonstrate that gigantol attenuates HFFD-induced MASH by promoting TFEB-dependent lipophagy and fatty acid oxidation, suggesting that gigantol, an edible plant-derived compound, is promising to be developed as a therapeutic drug for MASH in the future.