Targeting the LY6H-PI3K/AKT Autophagy Axis Suppresses HCC Malignancy and Reveals a Druggable Vulnerability

Hepatocellular carcinoma (HCC) is a highly lethal malignancy worldwide, with its initiation and progression closely tied to dysregulated autophagy. Lymphocyte antigen 6 family member H (LY6H), a glycosylphosphatidylinositol-anchored protein, is aberrantly expressed in multiple cancers, yet its functions and mechanisms in HCC remain undefined. Here, we demonstrate that LY6H is markedly upregulated in HCC specimens and that elevated LY6H correlates with poorer patient survival. Transcriptome analysis links LY6H expression to enhanced autophagic activity in HCC cells. Mechanistically, LY6H directly binds the p85 subunit of PI3K, promoting its phosphorylation at Tyr467, thereby activating the PI3K/AKT pathway and driving autophagy. Both in vitro and in vivo assays confirm that LY6H fosters autophagy-dependent proliferation of HCC cells. Importantly, we identify NSC243928 as a small-molecule inhibitor of LY6H, which effectively abrogates its tumor-promoting functions. Immunohistochemical studies reveal positive correlations among LY6H, ATG3, Beclin1, PI3K, and AKT expression in HCC tissues, with their co-overexpression predicting adverse prognosis. This work uncovers the critical LY6H–p-PI3K axis in HCC autophagy regulation and introduces a promising therapeutic candidate for targeting LY6H in liver cancer.