We greatly appreciate the thoughtful editorial by Dr. Leung and Dr. Lee [1], for their interests in our study and for providing insightful commentaries on our recent work published in Clinical and Molecular Hepatology [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 [3,4]. The 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 [5-7]. 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 KCTD17 on other Ras isoforms or its differential ubiquitination activity on these isoforms, leaving this as an open question for future research. Additionally, given the involvement of KRAS/MAPK signaling in immune modulation, it would be intriguing to explore whether targeting KCTD17 function in conjunction with immune signaling pathways could represent a promising area for research, particularly in the context of developing combination therapies that might offer more comprehensive treatment options for HCC patients, potentially leading to significantly improved outcomes.

Furthermore, Dr. Leung and Dr. Lee note that our study opens new avenues for the development of novel therapeutic agents targeting KCTD17. The design and synthesis of small-molecule inhibitors or protein degraders specifically aimed at inhibiting KCTD17 function could have significant clinical implications. Such agents may overcome the drug resistance observed with current therapies, offering new hope for patients with advanced HCC. In our study, we also observed that overexpression of KCTD17 conferred drug resistance to sorafenib and 5-fluorouracil by inhibiting the Akt and MAPK pathway. Given that first-line tyrosine kinase inhibitor treatments, such as sorafenib and Lenvatinib, only modestly extend the median overall survival of patients with advanced-stage HCC [8-11], and that second-line treatments with angiogenesis inhibitors similarly provide limited improvements in quality of life [12-15], the search for effective combination regimens-including the use of sorafenib alongside small-molecule inhibitors or protein degraders targeting KCTD17-may be crucial for improving survival outcomes in patients with advanced HCC. The translation of these findings from bench to bedside is eagerly anticipated by both the research and clinical communities, with the potential to bring significant advancements in patient care and treatment strategies, ultimately leading to better quality of life and prolonged survival for patients.

Once again, we extend our gratitude to Dr. Leung and Dr. Lee for their invaluable review. While our investigation has its limitations, our findings suggest a novel mechanism by which KCTD17 regulates Ras stability, positioning the KCTD17-Lztr1-Ras axis as a promising strategic approach for overcoming the complex challenges associated with HCC. Continued research into targeting KCTD17 in HCC patients will be instrumental in expanding the currently limited therapeutic options, ultimately aiming to improve patient outcomes and enhance the overall effectiveness of HCC treatment strategies potentially leading to more personalized and effective therapies for those affected by this challenging disease.