Metabolism-related ALDH1B1 acts as potential predictor and therapeutic target for primary gastrointestinal diffuse large B-cell lymphoma.

Primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) is the most common extra-nodal DLBCL. Metabolism-related factors have been associated with tumor progression, but the relationship between abnormal metabolism and prognosis of PGI-DLBCL remains unelucidated. In our study, consensus clustering based on metabolism-related genes classified PGI-DLBCL patients into two metabolic subtypes, and poor prognosis was associated with immunosuppressive microenvironment. A prognostic signature based on five metabolism-related genes (APOE, ALDH6 A1, PLOD2, IKBKB and ALDH1B1) was developed. Patients in high-risk group had a worse prognosis, with an immunosuppressive microenvironment. Moreover, 159 PGI-DLBCL patients were enrolled and divided into training cohort (n = 87) and validation cohort (n = 72). Univariate and multivariate Cox regression analysis showed metabolism-related factors were independent prognostic factors in PGI-DLBCL. A novel model (A-IPI score) combining APOA and NCCN-IPI was developed, and A-IPI score was better than NCCN-IPI score in predicting the prognosis of PGI-DLBCL patients. Furthermore, immunohistochemistry showed that ALDH1B1 was highly expressed in PGI-DLBCL and patients with high ALDH1B1 expression displayed worse prognosis. Moreover, cell proliferation assay revealed that the treatment with IGUANA-1, ALDH1B1 inhibitor, suppressed cell proliferation in DLBCL and IGUANA-1 exerted synergistic anti-tumor effects with PI3K inhibitor duvelisib. Additionally, we found that immune scores, ESTIMATE scores, and stromal scores were higher and the immune checkpoints (CTLA-4, PD-1, PD-L1) were down-regulated in patients with high ALDH1B1 expression. Collectively, our study constructed a novel metabolism-related prognostic model and highlighted the potential of metabolism-related gene ALDH1B1 as prognostic biomarker and drug target in PGI-DLBCL, providing new insights for the development of precision therapies in PGI-DLBCL patients.