FSTL1 contribute to aggressive clinical behavior in DLBCL may by activating the DIP2A/ICAM-1-mediated adhesion mechanism.

[INTRODUCTION] Despite improved outcomes in diffuse large B-cell lymphoma (DLBCL) with rituximab-based therapy, cell adhesion-mediated drug resistance (CAM-DR) remains a key mechanism of treatment resistance. The role of follistatin-like protein 1 (FSTL1) in CAM-DR has not been fully elucidated.

[METHODS] We conducted a retrospective analysis of newly diagnosed DLBCL patients treated with rituximab from 2019 to 2024, with special emphasis on FSTL1 expression and clinical features, and its underlying mechanism.

[RESULTS] FSTL1 was detectable in 74.5 % of patients. Its expression was significantly elevated in DLBCL patients compared to controls (P < 0.05) and was further increased in the RR-DLBCL group (P = 0.045). FSTL1 patients exhibited more adverse clinical features, including higher incidence of extranodal involvement, more advanced stage, elevated LDH levels, and bulky masses (all p < 0.05). FSTL1 expression patients revealed a shorter overall survival (OS) (p = 0.024) and progression-free survival (PFS) (p = 0.034), with similar trend in high FSTL1 expression (P < 0.05). In vitro, increased exogenous of FSTL1 contributed to DLBCL cell proliferation, vitality, and decreased the antibody-dependent cellular cytotoxicity (ADCC) effect, whereas FSTL1 silencing reversed this trend (P < 0.05). Pathway enrichment analysis revealed an association between FSTL1 and CAM-DR. Mechanistic experiments revealed that FSTL1 may be derived from secretion by cancer-associated fibroblasts (CAFs), interacts with DIP2A on DLBCL cells and promotes ICAM-1 expression, thereby contributing to drug resistance in DLBCL.

[CONCLUSION] Our findings indicate that elevated FSTL1 levels may contribute to advanced clinical characteristics and worse outcomes in DLBCL. FSTL1 contributes to drug resistance likely through DIP2a/ICAM-1-mediated adhesion mechanism.