Hypericin Suppresses Liver Cancer Through Autophagic Degradation of <scp>AKT</scp> and Eliciting Antitumor Immune Response

ABSTRACT Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy and the third leading cause of cancer‐related deaths worldwide, with high mortality and limited clinical treatment options. In this study, we identified hypericin as a potent inducer of HCC cell death by screening traditional Chinese Medicine Monomer Library screening. Hypericin, a natural photosensitizer derived from Hypericum perforatum , significantly inhibited the proliferation, migration, and colony formation of HCC cell lines, and induced apoptosis in vitro. In vivo, hypericin effectively suppressed tumor growth in Hepa1‐6 subcutaneous tumor and AKT/c‐Myc‐driven orthotopic mouse HCC models. Flow cytometry analysis revealed that hypericin treatment increased the CD8 + T cell proportion and activity within the tumor microenvironment. Combination therapy with hypericin and anti‐PD‐L1 antibody resulted in significant tumor growth inhibition and prolonged survival. Mechanistically, hypericin promoted the interaction between AKT and HSPA5, leading to autophagic degradation of AKT. This process inhibited the AKT/mTOR/S6 signaling pathway, downregulated the expression of downstream anti‐apoptotic proteins MCL‐1 and XIAP, and triggered mitochondria‐mediated apoptosis in HCC cells.