Collectively, these studies reveal a context-dependent duality in USP30’s regulation of mitochondrial dynamics: (1) It promotes DRP1-driven fission in HCC by counteracting K48-linked ubiquitination, and (2) modulates MFN1/2-mediated fusion through both inhibitory and stabilizing mechanisms depending on cellular stress conditions. This evidence concerns the gene DNM1L and hepatocellular carcinoma.