Personalized translational medicine: Investigating YKL-40 as early biomarker for clinical risk stratification in hepatocellular carcinoma recurrence post-liver transplantation

Abstract

Hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) presents a significant challenge, with recurrence rates ranging from 8% to 20% globally. Current biomarkers, such as alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), lack specificity, limiting their utility in risk stratification. YKL-40, a glycoprotein involved in extracellular matrix remodeling, hepatic stellate cell activation, and immune modulation, has emerged as a promising biomarker for post-LT surveillance. Elevated serum levels of YKL-40 are associated with advanced liver disease, tumor progression, and poorer post-LT outcomes, highlighting its potential to address gaps in early detection and personalized management of HCC recurrence. This manuscript synthesizes clinical and mechanistic evidence to evaluate YKL-40’s predictive utility in post-LT care. While preliminary findings demonstrate its specificity for liver-related pathologies, challenges remain, including assay standardization, lack of prospective validation, and the need to distinguish between malignant and non-malignant causes of elevated levels. Integrating YKL-40 into multi-biomarker panels with AFP and DCP could enhance predictive accuracy and enable tailored therapeutic strategies. Future research should focus on multicenter studies to validate YKL-40’s clinical utility, address confounding factors like graft rejection and systemic inflammation, and explore its role in predictive models driven by emerging technologies such as artificial intelligence. YKL-40 holds transformative potential in reshaping post-LT care through precision medicine, providing a pathway for better outcomes and improved management of high-risk LT recipients.

Key Words: Hepatocellular carcinoma recurrence; Liver transplantation; Personalized translational medicine; Biomarkers; YKL-40; Risk stratification

Core Tip: YKL-40 aligns with the principles of personalized translational medicine by offering a biomarker-driven approach to patient care. Its ability to provide liver-specific insights enables tailored post-liver transplantation surveillance and risk stratification, addressing the unique recurrence risks of individual patients. By integrating YKL-40 into multi-biomarker panels and predictive models, clinicians can refine therapeutic strategies, monitor disease progression more effectively, and personalize interventions for high-risk individuals. This targeted approach not only enhances clinical outcomes but also supports the broader shift toward precision medicine in transplantation, ensuring that care is both patient-specific and evidence-driven.

INTRODUCTION

Hepatocellular carcinoma (HCC) recurrence remains a formidable challenge in liver transplantation (LT), with global recurrence rates estimated between 8% and 20%[1]. Several risk factors have been identified in the development of HCC recurrence after LT, including tumor size, grade, differentiation, microvascular invasion, serum alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) levels[2,3]. While these markers enhance patient stratification, they lack precision in accurately predicting recurrence. Despite strict adherence to selection criteria for transplant candidates, the intricate and variable biology of HCC influences both the timing, manifesting as early or late recurrence, and its location, whether intrahepatic or extrahepatic, often complicating post-LT outcomes[4].

Advances in post-LT cancer treatment over the past decade have significantly improved survival rates, particularly with curative interventions[5]. However, these strategies remain reactive, addressing recurrence after clinical manifestation, rather than enabling early identification of high-risk individuals. The need for early, precise, and reliable prognostic tools is more urgent than ever to improve outcomes in this vulnerable population.

Emerging data highlight YKL-40, a glycoprotein involved in extracellular matrix (ECM) turnover and angiogenesis, as a promising biomarker for HCC recurrence. Elevated serum YKL-40 levels correlate with advanced liver disease and poorer outcomes[6,7]. Its unique role within the tumor microenvironment, including its impact on ECM remodeling and proangiogenic pathways, underscores its potential relevance to cancer progression and metastasis[8].

We hypothesize that serum YKL-40 levels could serve as an early predictive biomarker for HCC recurrence post-LT. Validating this biomarker through rigorous clinical research could revolutionize post-LT management by enabling precise risk stratification and guiding tailored intervention strategies. This manuscript synthesizes current clinical and mechanistic evidence on YKL-40, offering new insights into its role in HCC recurrence and its potential integration into personalized transplantation medicine.

YKL-40: A MULTIFACETED REGULATOR IN INFLAMMATION, FIBROSIS, AND TUMOR PROGRESSION

From repair to disease: YKL-40's dual role in tissue dynamics

YKL-40, also known as chitinase-3-like protein 1, is a glycoprotein from the glycosyl hydrolase family that, despite lacking enzymatic chitinase activity, exhibits significant biological activity in both physiological and pathological states[9]. It is secreted by macrophages, neutrophils, hepatic stellate cells (HSCs), and various cancer cells, underscoring its diverse cellular origins and roles[10].

In normal conditions, YKL-40 is vital for maintaining tissue integrity by promoting cell proliferation, migration, and ECM remodeling during injury, facilitating effective healing and functional recovery[11]. Additionally, it regulates immune responses by recruiting and activating immune cells, supporting a balanced inflammatory response necessary for tissue repair and regeneration[12]. These functions collectively preserve homeostasis and prevent pathological transitions.

Under pathological conditions, YKL-40 shifts from a protective to a pathogenic mediator[13]. It drives chronic inflammation by interacting with pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-alpha, and transforming growth factor-beta, amplifying signaling cascades that sustain prolonged inflammation[14]. This persistent inflammatory state exacerbates tissue damage, disrupts immune regulation, and creates conditions that facilitate disease progression. Such dynamic roles position YKL-40 as a crucial link between inflammation, fibrosis, and tumor development, offering insights into its dual functionality in health and disease.

Chronic inflammation to fibrosis: YKL-40 as the catalyst

YKL-40 facilitates the progression from chronic inflammation to liver fibrosis by modulating both immune cells and HSCs in a multifaceted manner[15]. Prolonged inflammation mediated by YKL-40 recruits macrophages and neutrophils, which exacerbate tissue injury through the release of reactive oxygen species and neutrophil extracellular traps[16]. These processes highlight YKL-40’s unique involvement in oxidative stress and metabolic imbalances within the liver, perpetuating a state conducive to fibrosis progression.

Simultaneously, YKL-40 activates quiescent HSCs, driving their transformation into myofibroblast-like cells that excessively produce ECM components such as collagen and fibronectin, leading to ECM accumulation and fibrotic scar formation[17]. Moreover, YKL-40 disrupts ECM homeostasis by skewing the balance between matrix metalloproteinases and their tissue inhibitors, further exacerbating fibrotic remodeling and structural liver alterations[18].

Additionally, YKL-40 enhances vascular remodeling through its regulation of vascular endothelial growth factor signaling. This angiogenic activity sustains the fibrotic microenvironment, providing vascular support that perpetuates the progression of liver fibrosis[19]. Collectively, these interconnected mechanisms establish YKL-40 as a central driver of fibrosis and chronic liver disease progression.

Immune modulation and tumor survival: YKL-40’s dual threat

YKL-40 contributes to immune modulation and tumor progression by altering macrophage polarization and T-cell activity. By driving macrophages toward the M2 phenotype, it promotes anti-inflammatory cytokine secretion, suppresses cytotoxic CD8+ T-cell activation, and facilitates angiogenesis, enabling tumor cells to evade immune detection[20]. Additionally, YKL-40 increases the recruitment of regulatory T cells (Tregs), further weakening anti-tumor immune responses. These interconnected mechanisms create a permissive microenvironment for tumor survival and metastasis, establishing YKL-40 as a critical mediator in the progression of chronic liver pathology, including advanced disease states such as HCC[21]. Mechanistic pathways linking YKL-40 to ECM remodeling and HCC recurrence are depicted in Table 1.

Table 1 Mechanistic pathways linking YKL-40 to extracellular matrix remodeling and hepatocellular carcinoma recurrence.

Mechanistic pathway	Role of YKL-40	Evidence	Ref.
Activation of hepatic stellate cells	Promotes activation and proliferation of hepatic stellate cells, driving liver fibrogenesis and contributing to extracellular matrix deposition	In vitro studies demonstrate direct effects on hepatic stellate cell activation	Nishimura et al[7]
TGF-β signaling pathway involvement	Regulates hepatocellular carcinoma cell proliferation, invasion, and metastasis through phosphorylation of SMAD2 and SMAD3 proteins	RNA-seq and Western blot analysis show activation of TGF-β signaling in HCC cell lines overexpressing YKL-40	Qiu et al[21]
Extracellular matrix remodeling	Enhances collagen deposition and matrix stiffening, creating a microenvironment conducive to tumor progression	Histological analysis indicates increased matrix stiffness and collagen deposition in YKL-40-rich liver tissues	Yan et al[15]
Lipid peroxide accumulation	Induces ROS and lipid accumulation, contributing to oxidative stress and tumor aggressiveness	Mouse cachectic models reveal elevated CHI3 L1 in muscle and circulation, linking lipid metabolism to HCC progression	Lu et al[20]
Macrophage activation and inflammation	Stimulates inflammatory responses, attracting macrophages to tumor sites and promoting angiogenesis and tissue remodeling	Immunofluorescence staining in NAFLD patients shows YKL-40 expression by macrophages in fibrotic liver tissue	Kumagai et al[18]

CHI3 L1: Chitinase-3-like protein 1; HCC: Hepatocellular carcinoma; LT: Liver transplantation; NAFLD: Non-alcoholic fatty liver disease; RNA-seq: Ribonucleic acid sequencing; ROS: Reactive oxygen species; TGF-β: Transforming growth factor-beta.

YKL-40: PRECISION BIOMARKER REDEFINING POST-LT RISK ASSESSMENT

Unlocking YKL-40’s potential as a biomarker

YKL-40 has emerged as a biomarker with targeted specificity, offering unique insights into liver disease progression and post-LT management that conventional markers like AFP and DCP cannot provide. Its multidimensional nature bridges systemic and liver-specific pathophysiological mechanisms, delivering actionable insights that enhance clinical decision-making and enable precise risk stratification for HCC recurrence post-LT[22].

Integrating YKL-40 into clinical workflows offers a transformative opportunity to enhance surveillance protocols, enable early detection of HCC recurrence post-LT, and personalize therapeutic strategies based on patient-specific risk profiles. By leveraging its unique attributes, YKL-40 could redefine post-LT management, improving outcomes through targeted and individualized care.

Bridging research gaps in YKL-40 translation

A detailed summary of studies evaluating YKL-40 as a biomarker for HCC recurrence and liver disease progression is presented in Table 2. Although YKL-40 demonstrates promising precision in reflecting hepatic fibrotic activity, its clinical translation remains hindered by several limitations. Notably, no large-scale, prospective studies have rigorously validated YKL-40's utility in predicting HCC recurrence post-LT. Current evidence primarily stems from retrospective analyses or small cohort studies, which lack the statistical robustness needed to reliably establish its sensitivity, specificity, predictive accuracy, and overall clinical applicability[5,7,9,13,23]. Another critical limitation lies in distinguishing between malignant and non-malignant causes of elevated YKL-40 levels in LT recipients, a challenge that complicates its broader application in post-LT surveillance.

Table 2 A detailed summary of studies evaluating YKL-40 as a biomarker for hepatocellular carcinoma recurrence and liver disease progression.

Ref.	Connection between YKL-40 and HCC recurrence	Strengths	Weaknesses	Clinical relevance	Ethical consideration
Pelizzaro et al[5]	Suggested potential relevance of YKL-40 for enhancing early detection of HCC recurrence in post-LT surveillance strategies tailored to pre-transplant history	Focused on post-LT surveillance, highlighting clinical utility	No direct investigation of YKL-40 levels in post-LT populations	Highlights potential integration of YKL-40 in post-LT surveillance models for early recurrence detection	The study adhered to ethical guidelines by ensuring informed consent and appropriate use of anonymized data. However, detailed ethical protocols (e.g., IRB approvals) were not explicitly outlined
Nishimura et al[7]	Emphasized YKL-40’s involvement in cancer cell proliferation, angiogenesis, and immune evasion as critical processes in tumor progression	Detailed insights into YKL-40’s role in cancer biology	Findings extrapolated to post-LT populations without direct evidence	Supports further exploration of YKL-40 in HCC progression and its role in tumor dynamics	Ethical considerations were not detailed in the study. Future research should incorporate transparent ethical protocols, including participant protections and considerations for data privacy
Qiu et al[21]	Demonstrated elevated YKL-40 levels in HCC patients, correlating with increased tumor proliferation, invasion, and metastasis through activation of TGF-β signaling	Established a clear link between YKL-40 and HCC progression through detailed mechanistic studies, highlighting its activation of TGF-β signaling and impact on cancer cell behavior	Limited focus on post-LT HCC recurrence and lack of large-scale clinical validation to confirm findings	Highlights the potential of YKL-40 as a biomarker for advanced liver disease and HCC, but its utility in post-LT surveillance remains unestablished	The study does not address patient consent or the implications of using YKL-40 as a biomarker in clinical decision-making
Kumagai et al[18]	Identified increased YKL-40 levels in patients with liver disease and cancer but lacked direct evidence for post-LT relevance	Established connection between YKL-40 and advanced liver disease/cancer	Limited focus on post-LT populations and confounding factors like graft rejection	Broadens understanding of YKL-40’s role in liver disease but lacks post-LT specificity	The study references adherence to ethical standards but lacks specific details on informed consent, patient protections, or approvals for human research
Zhu et al[23]	Demonstrated elevated YKL-40 levels in HCC patients post-curative resection were associated with shorter overall and recurrence-free survival	Strong prognostic associations with survival outcomes in HCC patients post-resection	Study excluded liver transplant recipients, limiting its direct relevance to post-LT settings	Indicates prognostic potential for recurrence-free and overall survival in HCC patients	Ethical compliance for human studies was reported, including IRB approval. However, the specifics of participant consent and the measures to protect vulnerable populations were not detailed
Lee at al[9]	Correlated elevated YKL-40 levels with liver disease severity but did not address liver transplant recipients or recurrence	Clear link between YKL-40 levels and disease severity	Did not explore HCC recurrence or post-LT settings	Provides foundational evidence for exploring YKL-40 in liver disease contexts	Ethical protocols were not explicitly described in the manuscript. This omission highlights a gap in documenting ethical compliance for studies involving human subjects. Future studies should ensure ethical transparency, particularly in vulnerable populations such as liver

HCC: Hepatocellular carcinoma; IRB: Institutional review board; LT: Liver transplantation; TGF-β: Transforming growth factor-beta.

Research priorities for precision and integration

To address existing limitations and fully assess YKL-40’s precision in liver disease and post-LT HCC recurrence, the need for robust, prospective, multicenter studies is paramount. Such investigations should focus on stratifying LT recipients based on recurrence risk, enabling a more nuanced understanding of its predictive capabilities across different clinical scenarios. Furthermore, these studies must systematically account for confounding factors, including graft rejection and systemic inflammation, which can influence YKL-40 levels and confound its interpretation.

Integrating YKL-40 into multi-biomarker panels with established markers such as AFP and DCP represents a promising approach. This combination could enhance predictive accuracy by leveraging the complementary strengths of each biomarker, paving the way for improved risk stratification and personalized management in post-LT surveillance.

Overcoming practical and logistical barriers

The clinical integration of YKL-40 as a biomarker hinges on a detailed understanding of its role within the intricate biological networks underlying HCC recurrence, alongside rigorous validation to establish its clinical relevance in post-LT populations. Standardizing measurement protocols, particularly for ELISAs, is crucial to ensure consistency and accuracy across institutions. Despite their widespread availability, ELISA-based assays require harmonization to overcome variability and improve reproducibility, especially in the complex setting of LT[24].

Patient-specific factors such as age, underlying comorbidities, and the use of immunosuppressive therapies further complicate the interpretation of YKL-40 levels, underscoring the necessity of robust protocols that contextualize YKL-40 measurements within broader clinical frameworks. Developing interpretative algorithms that integrate YKL-40 with other biomarkers and clinical parameters will be critical to enhancing its diagnostic precision.

From a practical standpoint, integrating YKL-40 testing into routine workflows demands significant infrastructure investments. This includes the creation of standardized assay kits and the establishment of clinically validated reference ranges tailored to post-LT populations. Addressing these logistical challenges will not only support the broader application of YKL-40 but also position it as a transformative tool in advancing post-LT patient care through more precise risk stratification and personalized management strategies.

Emerging technologies driving YKL-40 innovation

The integration of emerging technologies like machine learning and artificial intelligence (AI) offers transformative potential for biomarker discovery and application in clinical practice. These technologies can process large-scale datasets to uncover intricate patterns and associations, significantly enhancing the sensitivity and specificity of biomarkers such as YKL-40 in predicting HCC recurrence following LT[25]. By leveraging machine learning algorithms, YKL-40 can be effectively combined with established markers like AFP and DCP, creating predictive models tailored to individual patient profiles and supporting personalized post-LT management strategies[26].

AI platforms further refine the clinical application of YKL-40 by addressing inherent variability linked to patient-specific factors, such as age, comorbidities, or the use of immunosuppressive therapies. These tools streamline data interpretation, ensuring consistent and reliable utilization across diverse healthcare settings[27]. Additionally, AI-driven insights can aid in developing adaptive surveillance protocols and therapeutic interventions, aligning biomarker integration with the principles of precision medicine. Through these advancements, emerging technologies promise to enhance YKL-40's clinical utility, fostering its seamless incorporation into modern transplantation workflows.

Path to cost-effective implementation

Evaluating the cost-effectiveness of YKL-40 testing is crucial to determining its practical value in routine post-LT surveillance protocols. Cost-benefit analyses are necessary to assess whether the added clinical utility of YKL-40 justifies its financial and logistical implications. Such evaluations can guide decision-making on resource allocation and the scalability of YKL-40 testing within diverse healthcare systems[28].

CONCLUSION

YKL-40 holds the promise to revolutionize post-LT care, positioning itself as a cornerstone of precision medicine. Its unique translational potential extends beyond a single biomarker, offering profound insights into the recurrence and progression of HCC post-LT. By integrating YKL-40 into clinical workflows, the potential exists to redefine therapeutic strategies and improve patient outcomes through personalized care protocols. Fully realizing YKL-40’s potential requires rigorous research, innovative approaches, and dedicated resource allocation. Beyond transplantation medicine, its role in advancing multi-marker panels and precision protocols highlights its transformative potential to set new benchmarks in managing complex liver pathologies. Unlocking this biomarker’s capabilities could mark a paradigm shift in the care of high-risk LT recipients.