Tetrahydroberberine Suppresses Autophagy and Mitigates Doxorubicin‐Induced Ferroptosis in Hepatic Cells via cAMP ‐Epac1 Activation

This study investigated the hepatoprotective mechanism of tetrahydroberberine (THB) against doxorubicin (DOX)-induced liver injury. Using DOX-induced drug-induced liver injury (DILI) mouse models and AML12 hepatocytes, THB significantly reduced serum ALT/AST levels, alleviated hepatic pathological damage, and suppressed autophagic flux and ferroptosis. Mechanistically, THB activated the cAMP-Epac1 axis by directly binding Epac1, stabilizing FTH1 and upregulating GPX4, thereby blocking the crosstalk between ferritinophagy and ferroptosis. Network pharmacology suggested the cAMP pathway, and experimental validation identified Epac1 as the functional target. These mechanisms were validated using ESI-09, rapamycin, 3-MA, CETSA, and molecular docking. This study is the first to elucidate THB's hepatoprotective mechanism via the cAMP-Epac1/FTH1/GPX4 pathway, offering a natural product-based strategy for chemotherapy-associated liver injury.