Targeting the LY6H-PI3K/AKT autophagy axis suppresses HCC malignancy and reveals a druggable vulnerability.

Hepatocellular carcinoma (HCC) is a highly lethal malignancy worldwide, whose initiation and progression are closely associated with dysregulated autophagy. Lymphocyte antigen 6 family member H (LY6H), a glycosylphosphatidylinositol-anchored protein, is aberrantly expressed in multiple cancers; however, its functions and mechanisms in HCC remain undefined. Here, we demonstrate that LY6H is markedly upregulated in HCC specimens and that elevated LY6H expression correlates with poorer patient survival. Transcriptomic analyses link LY6H expression to enhanced autophagic activity in HCC cells. Mechanistically, LY6H directly binds the p85 subunit of PI3K, stabilizes its phosphorylation at Tyr467, and protects phosphorylated p85 from degradation, thereby promoting activation of the PI3K/AKT signaling pathway and driving autophagy. Functional assays in vitro, along with in vivo experiments utilizing the PI3K inhibitor LY294002, confirm that LY6H promotes HCC cell proliferation through a mechanism involving the PI3K/AKT pathway and autophagy. Importantly, we identify NSC243928 as a potential small-molecule inhibitor of LY6H, which effectively abrogates LY6H-driven autophagy and tumor-promoting functions both in vitro and in vivo. Immunohistochemical analyses reveal positive correlations among LY6H, ATG3, Beclin1, PI3K, and AKT expression in HCC tissues, and their co-overexpression predicts an adverse prognosis. Collectively, this work uncovers a critical regulatory role of the LY6H-p-PI3K-autophagy axis in HCC progression, elucidates the molecular mechanisms underlying LY6H-mediated oncogenic effects, and identifies NSC243928 as a promising therapeutic candidate for targeting LY6H in HCC.