# Phosphopeptidome Profiling of Human Plasma for Hepatocellular Carcinoma Biomarker Discovery

## TL;DR

Researchers identified a new set of phosphopeptides in human plasma that could serve as better biomarkers for detecting liver cancer than current methods.

## Contribution

The study introduces a novel phosphopeptide signature for hepatocellular carcinoma detection through plasma profiling.

## Key findings

- A statherin-derived phosphopeptide (DSSEEKFLR) showed high accuracy in distinguishing HCC from cirrhosis (AUC = 0.968).
- Multiple phosphopeptides from proteins like NST1, C4A, ITIH4, and AHSG demonstrated strong diagnostic potential (AUC > 0.80).
- Functional analysis linked the phosphopeptides to biological processes like coagulation, lipid metabolism, and LXR/RXR signaling.

## Abstract

Hepatocellular carcinoma
(HCC) remains a leading cause
of cancer
mortality, and current biomarkers such as alpha-fetoprotein (AFP)
lack diagnostic accuracy. Here, we report the first comprehensive
profiling of the plasma endogenous phosphopeptidome in HCC, cirrhosis,
and healthy controls using a digestion-free LC–MS/MS workflow.
From 60 plasma samples, 1,365 phosphopeptides corresponding to 549
proteins were identified and quantified. Among these, the statherin-derived
peptide DSSEEKFLR demonstrated outstanding discrimination between
HCC and cirrhosis (AUC = 0.968), outperforming AFP (AUC = 0.648).
Additional peptides, including PPGAPHTEEEGAE (NST1), YEYDELPAKDD (C4A),
SLPGESEEMMEEVD (ITIH4), and VSLGSPSGEVSHPRKT (AHSG), also showed high
accuracy (AUC > 0.80). Functional enrichment revealed perturbations
in acute-phase response, coagulation, lipid metabolism, and LXR/RXR
signaling. Collectively, this work defines a novel plasma phosphopeptide
signature that reflects disease-specific proteolytic and phosphorylation
dynamics, providing a foundation for developing biomarkers for early
detection and clinical monitoring of HCC.