Jung et al. [7] reported the upregulation of KCTD17 in both human and mouse HCC. This finding is clinically relevant; analysis of publicly available HCC datasets revealed the upregulation of this gene in HCC. KCTD17 overexpression was correlated with advanced tumor-node-metastasis stage. Survival analysis revealed that KCTD17 can serve as an independent prognostic marker for poor disease-free survival. These results show that KCTD17 is a potentially reliable diagnostic and prognostic marker for HCC. On the basis of these encouraging data, these researchers performed functional analyses via knockout and doxycyclineinducible KCTD17 knockdown approaches. Interestingly, the reduction in KCTD17 suppressed the proliferative, selfrenewal, and invasive abilities of HCC cells. Conversely, overexpression had the opposite effect. Notably, the overexpression of KCTD17 conferred resistance to sorafenib and 5-FU via the inhibition of the Akt and MAPK pathways.

To understand the molecular mechanism of KCTD17 in HCC, Jung et al. reported significant enrichment of Ras-related signaling features, including KRAS and extracellular signal-regulated kinase 1/2 signaling. Consistently, elevated levels of the Ras protein were detected despite unaltered mRNA levels, suggesting that KCTD17 regulates MAPK signaling through stabilizing the Ras protein. KCTD17 is a soluble, non-channel protein that functions as a substrate adapter for Cul3-based ubiquitin-conjugating enzyme E3 ligases and has a role distinct from its counterparts [8-10]. This observation, together with previous studies showing the role of leucine zipper-like transcription regulator 1 (Lztr1) in promoting the polyubiquitination and degradation of Ras family members by recruiting a Cul3 ubiquitin ligase complex [11-13], suggests that Kctd17 affects Ras stability by interfering with the Lztr1-Ras interaction. Consistent with this hypothesis, Kctd17 physically binds to Lztr1 and regulates its expression through ubiquitination, thereby affecting MAPK activation by stabilizing Ras. Lztr1 was found to be significantly downregulated in HCC cells [14].

To further examine the tumor-promoting role of KCTD17 in HCC, Jung et al. [7] demonstrated a significant decrease in tumor growth upon knockdown and knockout approaches. To determine the role of KCTD17 in HCC development, they administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) to hepatocyte-specific Kctd17 knockout (L-Kctd17) mice that were previously treated with diethylnitrosamine (DEN). Compared with wild-type mice, L-Kctd17 mice exhibited slower tumor growth. Next, on the basis of these encouraging data, they assessed the thera-peutic potential of targeting KCTD17. They employed hydrodynamic-induced and DEN-CDAHFD-induced HCC mouse models, and they demonstrated that reducing Kctd17 through the use of an antisense oligo suppressed the growth of HCC tumors without notable side effects; furthermore, this was accompanied by an increase in LZTR1 and a concurrent decrease in Ras expression.

Overall, this study describes an unprecedented role for KCTD17 in HCC, with new mechanistic insights and clinical implications. First, this study revealed that KCTD17 can function as a new diagnostic and prognostic marker for HCC. Second, KCTD17 expression is increased in different etiologies of HCC, such as those caused by viruses and MASLD. Third, this study provides new mechanistic insights into how KCTD17 regulates the Ras signaling pathway (Figure 1). Finally, this study provides a novel therapeutic strategy for HCC treatment via the suppression of KCTD17 expression. Although the in vitro and in vivo data obtained by Jung et al. [7] are novel and encouraging, several questions still need to be explored. Given the existence of several isoforms of Ras proteins, including NRAS, KRAS, and HRAS [15], it is important to determine whether KCTD17 affects the expression of isoforms in addition to KRAS. Since KRAS/MAPK signaling has been found to play a role in immune modulation [16], targeting KCTD17 may complement current immune therapies. Considering the significant therapeutic potential of targeting KCTD17 in HCC, researchers are eagerly awaiting the synthesis of small-molecule inhibitors and protein degraders against KCTD17 to facilitate the translation of these findings.