Correspondence to editorial on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”

Dear Editor,

We sincerely appreciate the insightful and comprehensive editorial by Xie et al. [1] regarding our study on GULP PTB domain-containing engulfment adaptor 1 (GULP1) as a novel diagnostic and predictive biomarker in hepatocellular carcinoma (HCC). It is a great honor to have our work recognized in Clinical and Molecular Hepatology, and we deeply appreciate the editorial’s thorough analysis and valuable perspectives. Their discussion on GULP1’s dual role as both a biomarker and an oncogenic driver, as well as its potential as a therapeutic target, aligns closely with our vision of translating these findings into clinical applications.

HCC is characterized by a notably high recurrence rate compared to other malignancies, making the identification of reliable biomarkers for recurrence prediction a critical research priority [2-4]. The primary objective of our study was to develop a recurrence-associated signature that could effectively predict HCC recurrence and guide clinical decision-making. To achieve this, we applied a multi-omics approach, integrating genomic, transcriptomic, and proteomic analyses, and employed machine learning-based modeling to identify a 15-gene risk score for recurrence prediction. Among these genes, GULP1 emerged as the most significant candidate, showing a strong association with HCC recurrence and prognosis [5].

Importantly, we also found that serum GULP1 levels, in combination with alpha-fetoprotein (AFP), improved diagnostic accuracy for HCC detection [5]. We subsequently expanded our patient cohort to evaluate serum GULP1 prospectively, and preliminary results reaffirm its elevated levels in HCC patients compared to controls, complementing AFP in detecting early HCC. As Dr. Xie et al. [1] suggested, establishing standard reference ranges and cutoff values for serum GULP1 will be an important next step to facilitate its translation into clinical practice.

Another key point highlighted in the Editorial was GULP1’s pro-tumorigenic role in HCC, and our data strongly support this [1]. We observed that altering GULP1 expression in HCC cell lines significantly affected cell proliferation and epithelial-mesenchymal transition (EMT) markers, corroborating GULP1’s influence on tumor aggressiveness . Specifically, GULP1 knockdown attenuated cell growth and invasive properties, whereas overexpression accelerated these phenotypes. Mechanistically, we reported that GULP1 modulates the ADP-ribosylation factor 6 (ARF6) and Wnt/β-catenin signaling pathways, which are known drivers of HCC progression [6]. Xie et al. [1] insightfully noted that GULP1’s interaction with these pathways could underlie its impact on EMT and metastasis. We concur and would add that GULP1 may function as an adaptor linking cell-surface signals to downstream oncogenic pathways. Interestingly, the context- dependent nature of GULP1’s function across cancers further illustrates its multifaceted role. For example, in ovarian cancer cells GULP1 is required to maintain sensitivity to TGF-β-induced growth arrest [7]. In urothelial carcinoma, downregulation of GULP1 levels induces cell growth, predominantly via activation of the NRF2–KEAP1 signaling pathway [8]. However, our findings revealed its different roles in HCC, in which GULP1 promotes tumor growth and dissemination. This dualistic behavior underscores the complexity of GULP1’s biology and warrants deeper investigation into how tumor context dictates its function. As noted, GULP1’s contribution to HCC progression makes it an attractive candidate for therapeutic intervention. While no direct GULP1 inhibitors are currently available, our findings suggest alternative strategies. One approach is to target the downstream effects of GULP1: for instance, inhibiting Wnt/β-catenin signaling or ARF6 activation could potentially mimic the impact of GULP1 suppression on tumor behavior. Given that GULP1 is an adaptor for the phagocytic receptor LRP1 (implicated in TGF-β signaling and cell migration), disrupting the GULP1–LRP1 interaction might impair pro-tumorigenic signaling in HCC [9,10]. Additionally, Xie et al. [1] proposed investigating how GULP1 interacts with other oncogenic pathways, such as Notch signaling, to further elucidate its role in HCC progression [11]. We strongly agree that exploring these molecular interactions could provide deeper mechanistic insights and identify novel therapeutic targets.

Dr. Xie’s letter provided valuable insights; however, our study still has certain limitations [12]. One key aspect is the need for prospective clinical validation of GULP1 as a biomarker. We acknowledge that our current evidence is based on retrospective analyses and controlled cohorts. To address this, we will conduct a prospective study enrolling patients at risk for HCC (e.g., those with cirrhosis or chronic hepatitis) to monitor GULP1 levels over time and correlate them with HCC development and recurrence. This will help determine the predictive power of GULP1 in real-world surveillance settings. Additionally, as suggested, we are examining the role of GULP1 in the tumor microenvironment. Given GULP1’s origin as an engulfment adapter protein, it may influence how cancer cells interact with immune cells (for instance, through efferocytosis of apoptotic cells or modulation of macrophage activity) [9,10]. Clarifying these interactions could reveal whether GULP1 contributes to an immunosuppressive milieu in HCC, further reinforcing its value as a therapeutic target.

In summary, we strongly agree with Dr. Xie’s characterization of GULP1 as a multifaceted player in HCC. Our findings establish GULP1 as a valuable diagnostic and prognostic biomarker and implicate it in key oncogenic processes that drive HCC progression. Xie et al. [1]’s perspective has aptly highlighted the translational potential of these insights. We remain committed to further research that will validate GULP1’s clinical applications and explore therapeutic avenues to target the GULP1-associated pathways. By addressing the points raised in the editorial – from improving diagnostic frameworks to pioneering targeted interventions – we aim to accelerate the incorporation of GULP1 into personalized HCC management, ultimately improving patient outcomes.

We once again thank the editorial authors for their supportive and constructive commentary. Such academic dialogue not only reinforces the significance of our work but also encourages us to further explore unanswered questions. We are optimistic that with continued research, GULP1 will transition from an exciting biomarker discovery to a practical tool and target in the fight against HCC.

Abbreviations

AFP

alpha-fetoprotein

ARF6

ADP-ribosylation factor 6

GULP1

GULP PTB domain containing engulfment adaptor 1

HCC

hepatocellular carcinoma