Background: SLC1A5, a ferroptosis regulator gene, plays a dual role in cancer regulation. However, the roles of SLC1A5 in pancreatic adenocarcinoma (PAAD) remain elusive. Methods: SLC1A5's expression and somatic mutation information were determined by TCGA, GEO, Oncomine, and cBioPortal databases. Its prognostic value was assessed in TCGA cohort and was validated in three independent cohorts. The effects of SLC1A5 on the tumor immune microenvironment were analyzed by the CIBERSORT algorithm, ssGSEA method, and TISIDB and TIMER databases. The "oncoPredict" R package, TIDE algorithm, ImmuCellAI online tool, and GSE35141 and GSE59357 datasets were used to ascertain its therapeutic correlations. GSEA and Western blot were applied to reveal the effects of SLC1A5 on the mTORC1 signaling pathway and ferroptosis process. The biofunctions of SLC1A5 were assessed by MTT, wound-healing, Transwell, and xenograft assays. Results: SLC1A5 was significantly upregulated in the PAAD samples but was not commonly accompanied with somatic mutation (2.3%). Overexpression of SLC1A5 led to a poor prognosis and was identified as an independent prognostic factor. Moreover, high SLC1A5 expression suppressed the antitumor immune process by changing the infiltrating levels of immune cells. As for therapeutic correlations, SLC1A5 was related to the efficacy of dasatinib, sunitinib, sorafenib, and imatinib but may not predict that of radiotherapy, chemotherapeutic drugs, and immune checkpoints inhibitors (ICIs). Notably, the overexpression of SLC1A5 could activate the mTORC1 signaling pathway and may increase the cellular sensitivity to ferroptosis. Finally, the overexpression of SLC1A5 markedly promoted proliferation, migration, and invasion of pancreatic cancer cells. At the in vivo level, SLC1A5 deletion inhibited tumor growth in a mice xenograft model. Conclusions: SLC1A5 prefers to play as an accomplice rather than an opponent in PAAD. Our findings provide novel insights into PAAD treatment.

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