Combined inhibition of CMA and SHH pathway had a synergically therapeutic effect on SHH-MB.<h4>Conclusions</h4>These results establish CMA and USP9X as pivotal regulators of SHH medulloblastoma MB progression, emphasising their potential as novel therapeutic targets for medulloblastoma, and combinatorial inhibition of CMA and Smoothened (SMO) may provide a strategy to overcome intrinsic or acquired resistance to SMO monotherapy in SHH-MB.<h4>Key points</h4>Deubiquitinase USP9X suppresses SHH Medulloblastoma progression by facilitating SUFU ubiquitination. This evidence concerns the gene SMO and medulloblastoma.