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

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.

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.