Structure-based development of a peptide inhibitor targeting fibroblast activation protein for the treatment of...

Rectal cancer progression and resistance are linked to the tumor microenvironment, making FAP a stromal target for peptide inhibitor development. This study integrated transcriptomic data from 1236 rectal cancer and normal rectal tissue samples with random forest- and LASSO-based target prioritization and structure-based peptide screening. FAP ranked first in the six-dimensional scoring system, with a comprehensive score of 0.89. Its expression was consistently increased in TCGA-READ, GSE38718, and GSE87211 cohorts by 4.32-fold, 3.87-fold, and 4.15-fold, respectively, and showed diagnostic performance with an AUC of 0.82. High FAP expression was associated with advanced stage, lymph node metastasis, lower 5-year overall survival, stromal enrichment, and immunosuppressive cell infiltration. Structure-based screening of 10,000 peptides identified 32 candidates. Among them, Pep17 showed relatively stable binding during the 100 ns molecular dynamics simulation, with a Top 1 cluster population of 42.3% and the most favorable MM/PBSA binding free energy among the three tested peptides (-4.82 ± 0.36 kJ/mol). Pep17 was therefore prioritized as a promising FAP-targeted peptide candidate for experimental validation.

The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05061-x.