We sincerely appreciate the thoughtful and comprehensive editorial by Dr. Ji Eun Han et al.regarding our study on MET promotes hepatocellular carcinoma (HCC) development via Tribbles Pseudokinase 3 (TRIB3)-mediated forkhead box O1 (FOXO1) degradation [1,2]. Their critical appraisal highlights the clinical significance of our findings and presents several key considerations that may help shape future investigations into the MET–TRIB3–FOXO1 regulatory network. We are honored to contribute to this academic exchange that advances the collective understanding of MET-driven liver cancer progression and potential intervention strategies.

MET overexpression is observed in approximately 30–50% of HCC cases [3] and is closely linked to the high-proliferation subclass of this malignancy [4]. Nonetheless, the underlying molecular mechanisms remain incompletely elucidated, hindering the development of effective MET-targeted therapies. Our investigation aimed to dissect the oncogenic functions of MET and understand why MET inhibition has yielded limited success clinically. Utilizing a hydrodynamic tail vein injection (HTVi) model co-expressing MET and β-catenin, we identified TRIB3 as a pivotal downstream effector. Mechanistically, MET signaling upregulated TRIB3 via the ERK–SP1 axis, as confirmed by chromatin immunoprecipitation and pharmacologic inhibition studies. Subsequent experiments demonstrated that TRIB3 engages the E3 ligase COP1, promoting proteasomal degradation of FOXO1—a well-characterized tumor suppressor [5,6]. This interaction was conserved across several cancer cell types, including hepatocellular, colorectal, and breast cancer lines, suggesting broader oncogenic implications. The TRIB3-COP1-FOXO1 complex contributes to MET-induced proliferation and invasion by elevating key downstream targets such as MET, CCND1, and TWIST1 [7-9]. This regulatory cascade forms a self-reinforcing loop that amplifies malignant behavior. We further evaluated the therapeutic relevance of TRIB3 by employing adeno-associated virus serotype 8 (AAV8) [10] to silence its expression in vivo, which resulted in substantial tumor suppression and prolonged survival. These findings provide a rational for the development of small molecules that either inhibit TRIB3 directly or block its interaction with COP1.

In our patient cohort of 75 HCC cases, TRIB3 expression positively correlated with MET and SP1 levels, while inversely associated with FOXO1. Patients exhibiting high levels of MET and TRIB3 had the poorest outcomes in terms of overall and recurrence-free survival, emphasizing the prognostic utility of this axis. In an effort to translate these insights into clinical tools, we are currently designing a multiplex immunohistochemistry panel to quantitatively assess MET, TRIB3, and FOXO1 expression in biopsy samples, which may serve as a predictive model for MET-targeted therapy response.

Dr. Ji Eun Han’s letter also highlighted avenues for further research. One important implication involves exploiting TRIB3 and FOXO1 as therapeutic targets. Our in vivo silencing approach via AAV8-shTRIB3 restored FOXO1 expression and curbed tumor growth. Consistent with Dr. Han et al.’s suggestions, developing pharmacologic inhibitors specific for TRIB3 or agents that preserve FOXO1 stability could offer new therapeutic strategies. In addition, investigating whether TRIB3 contributes to resistance mechanisms against immunotherapy may reveal synergistic effects when combined with immune checkpoint inhibitors. We acknowledge certain limitations of our study. For instance, the use of the HTVi model with overexpression of MET and β-catenin may not fully capture tumor heterogeneity observed in human HCC. To address this, we are extending validation efforts to orthotopic patient-derived xenografts harboring endogenous oncogenic alterations. Moreover, our current cohort mainly comprises HBV-associated HCC. Given the increasing prevalence of non-alcoholic steatohepatitis related HCC, we plan to evaluate whether similar pathway dynamics occur across diverse etiologies. Additionally, since FOXO1 plays a central role in regulating cell cycle arrest [11] and oxidative stress balance [12], understanding how its dysregulation contributes to therapeutic resistance remains a top priority.

In conclusion, we strongly agree with Dr. Ji Eun Han’s characterization of the TRIB3 as a crucial oncogenic mediator in MET-driven HCC. Our findings shed light on the biological basis for MET-targeted therapy failure and suggest new directions for individualized treatment strategies. We are deeply grateful to the editorial authors for their incisive analysis, which has encouraged us to further explore TRIB3’s role in the tumor microenvironment.

Once again, we express our heartfelt thanks to Dr. Ji Eun Han and colleagues for their constructive and inspiring commentary.