Adaptor AP4M1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis through USP15-mediated...

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, highlighting the urgent need for novel diagnostic and therapeutic targets. In this study, through integrated proteomic profiling, we identify AP4M1 as a potential therapeutic vulnerability for HCC and characterize its upstream regulatory and downstream effector mechanisms. We show that AP4M1 is markedly upregulated in HCC, correlates with unfavorable prognosis, and is functionally involved in driving HCC progression. Mechanistically, the deubiquitinase USP15 stabilizes AP4M1 by removing K11- and K48-linked polyubiquitin chains at lysine 163 (K163). Additionally, MINK1-mediated phosphorylation of AP4M1 at threonine 69 (T69) is critical for its interaction with GPX4. Through upregulating GPX4, AP4M1 reduces intracellular lipid peroxidation, thereby suppressing ferroptosis and facilitating HCC tumorigenesis and progression. Importantly, combined treatment with the USP15 inhibitor USP15-IN-1 and the GPX4 inhibitor RSL3 exhibits potent anti-tumor efficacy in both in vitro and in vivo models, underscoring the therapeutic potential of targeting the AP4M1 axis in HCC. Collectively, this study delineates the USP15/AP4M1/MINK1/GPX4 axis as a previously unrecognized ferroptosis-suppressive pathway that promotes HCC progression, providing a critical theoretical basis for AP4M1-targeted therapeutic strategies in HCC.