Cordycepin Alleviates Non Alcoholic Fatty Liver Disease Progression by Stabilizing GCH1 to Inhibit Ferroptosis.

To investigate the effects and targets of cordycepin (COR) in alleviating non-alcoholic fatty liver disease (NAFLD). High-fat diet was used to induce NAFLD in mice, and after COR gavage administration, changes in liver function, glucose and lipid metabolism, and ferroptosis-related signaling were detected. In vitro, palmitic acid (PA) and oleic acid (PSA) were combined to induce hepatocyte lipid injury. The effect of COR on hepatocyte ferroptosis was examined. GCH1 conditional knockout mice (GCH1-CKO) and hepatocyte models were constructed, and AAV9-GCH1 was used to construct GCH1 overexpression mouse models to verify the effect of GCH1 on NAFLD. CETSA-WB, co-immunoprecipitation, and DARTS were employed in the COR-GCH1 interaction and mechanism studies to validate the targeted binding relationship between COR and GCH1. Animal-level studies showed that COR could improve glucose and lipid metabolism and liver function damage in mouse NAFLD, inhibit ferroptosis occurrence and lipid peroxidation injury. Cell-level results showed that COR could inhibit hepatocyte ferroptosis. The ferroptosis-inhibiting effect of GCH1 is independent of GPX4 and other signals; GCH1 directly inhibits reactive oxygen free radicals and suppresses lipid metabolism peroxidation damage. COR's effects are not related to classical anti-ferroptosis signals such as GPX4 and Nrf2, but only related to GCH1. COR can target the GCH1 K155 site, stabilize protein levels by inhibiting GCH1 ubiquitination degradation, and when GCH1 is knocked out, COR's effects are antagonized. GCH1 has a protective role in NAFLD, and this effect is independent of classical GPX4 signaling. COR can target the GCH1 K155 site, inhibit GCH1 ubiquitination thereby preventing protein degradation and exerting protein stabilization. COR elevates GCH1 levels to inhibit ferroptosis. COR is a small molecule with potential for treating NAFLD.