GULP1: New hope for hepatocellular carcinoma: Reply to correspondence on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”

Dear Editor,

Recently, the paper entitled “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma” was featured in Clinical and Molecular Hepatology, and it presented a very interesting and attractive discussion on the potential role of GULP PTB domain-containing engulfment adaptor 1 (GULP1) as a candidate dual biomarker for both diagnoses and prediction in hepatocellular carcinoma (HCC) [1]. This work provides a better understanding of HCC biology as well as new insight into clinical translation. In response, we wrote an editorial entitled “GULP1, A Multifaceted Diagnostic Biomarker and Potential Therapeutic Target in Hepatocellular Carcinoma” and the authors have provided a detailed reply to it [2,3]. Therefore, we were pleased to receive the authors’ correspondence and am also glad to engage in an active discussion with them about this study again. We deeply appreciate the authors for their detailed discussion of our editorial and for their thorough response.

First, Dr. Kim et al. demonstrated that combining serum GULP1 with alpha-fetoprotein (AFP) detection significantly enhances diagnostic accuracy for early-stage HCC [1]. Subsequent validation in an expanded patient cohort further confirmed the synergistic effect of this dual-biomarker approach. Importantly, the integration of GULP1 monitoring significantly improved early detection algorithms for AFP-negative HCC cases, addressing current limitations in diagnostic sensitivity for this area. This breakthrough raises an important clinical consideration: longitudinal monitoring of GULP1 levels during HCC progression and treatment may unlock additional clinical utilities of GULP1. The authors’ proposed prospective study—tracking GULP1 dynamics in high-risk populations—could establish critical correlations between GULP1 and HCC progression. We eagerly anticipate the potential revelation of GULP1’s predictive value in this longitudinal investigation.

Secondly, we endorse Dr. Kim et al.’s proposition that GULP1 likely functions as a critical signaling nexus within the tumor microenvironment, bridging membrane-proximal events with core oncogenic pathways [1]. This molecular positioning makes GULP1 particularly attractive for investigating cancer-immune interactions. Given its role as an engulfment adapter protein, GULP1 may mediate the interaction between tumor cells and immune cells like macrophages, potentially fostering immunosuppressive niche formation [4]. Key investigational priorities include identifying GULP1’s impact on HCC-associated macrophage functions—particularly efferocytosis competence and cytokine secretion dynamics—and establishing potential correlations between GULP1 expression profiles and clinically actionable biomarkers such as PD-L1 expression or immune checkpoint inhibitor responsiveness. Such investigations could reveal novel combinational therapeutic strategies targeting both malignant cells and their immunosuppressive niches.

Thirdly, the dual role of GULP1 across cancer types, as reported by Dr. Kim et al., reveals its remarkable biological complexity. While functioning as an oncogene promoting tumor progression in HCC, GULP1 acts as a tumor suppressor gene in ovarian and urothelial cancers [1,5,6]. This context-dependent behavior highlights how tissue-specific signaling environments can decide divergent functions of the same gene. Such findings provide critical insights for personalized medicine, suggesting that understanding these multifaceted behaviors of one gene could lead to cancer-type-specific therapies targeting shared molecular targets.

Fourthly, we strongly endorse Dr. Kim et al.’s proposed alternative strategies to address the current lack of direct GULP1 inhibitors. Mechanistically, as an upstream regulator of ADP-ribosylation factor 6 (ARF6) and Wnt/β-catenin signaling, GULP1-driven HCC may be vulnerable to combination therapies targeting these downstream effectors [1,7]. A promising approach involves evaluating clinically available ARF6 inhibitors (e.g., SecinH3, NAV-2729) alongside Wnt pathway antagonists (e.g., vantictumab, PRI-724) in GULP1-activated HCC models [8,9]. Furthermore, based on our previous editorial, synergistic targeting of the Notch pathway—a key mediator of HCC stemness and chemoresistance—could enhance drug efficacy while minimizing resistance development [2]. The integration of advanced preclinical models, particularly patient-derived tumor organoids, will accelerate both inhibitor screening and personalized treatment regimen optimization for GULP1-driven HCC [10].

In conclusion, Dr. Kim et al. have successfully established GULP1 as a dual-function biomarker for HCC diagnosis and prognosis. By addressing the above critical challenges, including prospective clinical validation, microenvironmental crosstalk decoding, and pathway-specific targeting, this discovery holds strong potential for clinical translation. We anticipate that GULP1-driven strategies may address current gaps in HCC management, particularly in early detection and personalized therapy, ultimately improving global patient outcomes.

Abbreviations

AFP

α-fetoprotein

ARF6

ADP-ribosylation factor 6

GULP1

GULP PTB domain-containing engulfment adaptor 1

HCC

hepatocellular carcinoma