Polygoni Cuspidati Rhizoma et Radix extract activates TFEB and alleviates hepatic steatosis by promoting autophagy

Hepatic steatosis, characterized by excessive lipid accumulation in the liver, can be ameliorated by autophagy activation. Polygoni Cuspidati rhizome et Radix (PCRR), traditionally used to treat atherosclerosis, hepatitis, and gallstones, has recently demonstrated anti-steatotic effects in the liver. However, the active compounds and underlying mechanisms remain unclear. This study investigated whether PCRR water extract improves steatosis by modulating hepatic autophagic flux. We found that PCRR water extract promoted autophagic flux, enhanced lysosomal biogenesis, and alleviated lipid accumulation in the liver cell lines as well as in the livers of rats with steatosis. Mechanistically, PCRR water extract inhibited mechanistic target of rapamycin complex 1 (mTORC1) activity, leading to dephosphorylation and subsequent nuclear translocation of transcription factor EB (TFEB), a key regulator of lipophagy. TFEB knockdown attenuated PCRR-mediated lipophagy promotion in the liver cell lines. Furthermore, chloroquine (CQ)-mediated autophagy blockage abrogated the therapeutic effect of PCRR against hepatic steatosis in high-fat diet (HFD)-fed rats. These findings suggest that PCRR water extract acts as a novel autophagy enhancer and holds therapeutic potential for hepatic steatosis.