Suppressor with morphogenetic effect on genitalia 7 (SMG7) drives hepatocellular carcinoma progression through context-dependent nonsense-mediated decay (NMD) dysregulation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major risk factor for hepatocellular carcinoma (HCC), yet the molecular mechanisms linking metabolic stress to tumor progression remain poorly defined. RNA surveillance pathways, including nonsense-mediated decay (NMD), may represent a relevant but unexplored regulatory layer in this context. In this study, we analyzed the expression of NMD components across multiple human HCC and MASLD cohorts, identifying suppressor with morphogenetic effect on genitalia 7 (SMG7) as a key regulator of NMD associated with HCC progression. In vitro functional assays, NMD target expression, transcriptomic profiling, and weighted gene co-expression network analysis (WGCNA) were used to identify downstream pathways and mediators. More than 40% of NMD components were dysregulated in HCC. Among them, SMG7 was consistently upregulated across HCC and MASLD cohorts, induced by lipotoxic stress, and identified as a hub gene in HCC transcriptional networks. SMG7 overexpression promoted proliferation, migration, and clonogenicity, whereas its silencing reduced tumor aggressiveness in a context-dependent manner inversely associated with UPF1 levels. Combined depletion of SMG7 and UPF1 suppressed aggressive traits in vitro and limited tumor growth in vivo. Transcriptomic and network analyses identified Z-DNA-binding protein 1 (ZBP1) as a downstream mediator of SMG7 dysregulation in SNU-387 HCC cells, a finding further supported by functional rescue experiments. These results identify the SMG7-ZBP1 axis as a metabolic stress-responsive pathway linking NMD dysfunction to liver tumor progression and highlight NMD modulation as a therapeutic strategy to restrain tumor aggressiveness while enhancing tumor immunogenicity.