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  4. Vol 4, Issue 1, 2026

Targeting the CTSS/CAPN6 axis: a multi-omics guided strategy for diagnosis and immunomodulatory therapy in recurrent implantation failure

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DOI: 10.23977/medbm.2026.040116 | Downloads: 0 | Views: 11

Author(s)

Qi Lang 1, Jinran Li 1, Kai Wang 1, Hui Tang 1

Affiliation(s)

1 Clinical Laboratory Center, the First Affiliated Hospital of Guilin Medical University, 109 Ring City North Second Road, Guilin, Guangxi, 541004, China

Corresponding Author

Hui Tang

ABSTRACT

Recurrent implantation failure (RIF) remains a major clinical challenge in assisted reproduction, largely owing to the lack of validated biomarkers and mechanism-based therapies. The present study aimed to identify key molecular drivers of RIF and to discover diagnostic biomarkers and therapeutic targets by integrating multi-omics bioinformatics with experimental validation. Three endometrial transcriptomic datasets (GSE103465, GSE111974, GSE188409) from RIF patients and fertile controls were analyzed using a streamlined workflow that comprised batch correction and differential expression analysis (n = 651), WGCNA identifying the RIF-associated turquoise module (r = 0.43, P = 4 × 10⁻⁴), Random Forest prioritization of CTSS and CAPN6, ROC-based diagnostic evaluation, and functional interpretation via GO/KEGG, ssGSEA, GSVA, and drug enrichment; in addition, CTSS and CAPN6 protein expression was validated by immunohistochemistry (IHC) in independent clinical endometrial samples. CTSS and CAPN6 were robustly identified as upregulated and functionally linked RIF drivers, and a two-gene model achieved an AUC of 0.835 (95% CI: 0.731–0.925), outperforming single markers. Both genes were implicated in lysosomal proteolysis, antigen processing, and immune modulation. Notably, the RIF endometrium exhibited elevated M0 macrophages and reduced monocytes/resting mast cells, with CAPN6 strongly correlated with M0 abundance (P < 0.001). Drug enrichment highlighted protease inhibitors, including boceprevir, as top-ranked candidates, and IHC confirmed significantly higher CTSS and CAPN6 protein levels in RIF versus controls (both P < 0.001). In conclusion, CTSS and CAPN6 serve as validated diagnostic biomarkers for RIF; their involvement in proteolytic–immune crosstalk, together with the association of CAPN6 with macrophage infiltration, supports targeted immunomodulatory strategies, while the potential repurposing of boceprevir highlights the translational value of the analytical framework.

KEYWORDS

Recurrent implantation failure; CTSS; CAPN6; Biomarkers; Machine learning; Immune infiltration

CITE THIS PAPER

Qi Lang, Jinran Li, Kai Wang, Hui Tang. Targeting the CTSS/CAPN6 axis: a multi-omics guided strategy for diagnosis and immunomodulatory therapy in recurrent implantation failure. MEDS Basic Medicine (2026). Vol. 4, No. 1, 121-130. DOI: http://dx.doi.org/10.23977/medbm.2026.040116.

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