Correspondence to editorial on “KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression”

2 regarding the role of KCTD17 in progression of hepatocellular carcinoma (HCC).As the editorial highlights, identifying reliable biomarkers and developing novel therapeutic strategies are urgently needed for HCC, especially given that most patients with HCC are diagnosed at an advanced stage, where therapeutic options are severely limited. 3,4The findings presented in our study are therefore both groundbreaking and significant, as our research not only highlights KCTD17 as a novel diagnostic and prognostic biomarker but also unravels its mechanistic role in the Ras signaling pathway, thereby providing new avenues for therapeutic intervention, and significantly expanding our understanding of the molecular mechanisms underlying HCC progression and potential treatment strategies.While our findings are promising, several important questions remain unanswered, meriting further investigation.As Dr. Leung and Dr. Lee have pointed out, one critical area that requires additional exploration is the potential role of KCTD17 in regulating the specificity of Ras isoforms.Previous studies have demonstrated that leucine zipper-like transcription regulator 1 (Lztr1) promotes the polyubiquitination and degradation of Ras family members by recruiting a Cul3 ubiquitin ligase complex, thereby inhibiting Ras/ MAPK signaling. [5][6]6][7] In our study, we found that KCTD17 interacts with Lztr1, increasing its ubiquitination, which in turn inhibits Lztr1-mediated Ras ubiquitination.Given that Lztr1 functions as a "multiple Ras killer protein" regardless of the Ras isoform involved, 5 and that KCTD17 induces Lztr1 proteasomal degradation, it is plausible that KCTD17 could regulate multiple Ras isoform.Indeed, our study shows that KCTD17 promotes both H-Ras and K-Ras. 2 However, we have not yet investigated the effects of