Se-methylselenocysteine induces NRF2-ATF4 stress signaling and ferroptosis-associated remodeling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound resistance to therapy, driven in part by its capacity to adapt to oxidative, metabolic, and proteotoxic stress. In this study, we investigated how the redox-active selenium compound Se-methylselenocysteine (MSC), following metabolic activation by kynurenine aminotransferase 1 (KYAT1), reprograms stress-response pathways in PDAC cells. RNA sequencing across three PDAC cell lines revealed pronounced, phenotype-dependent transcriptional adaptations upon MSC exposure. CAPAN-2 cells predominantly activated an NRF2-centered antioxidant response accompanied by ferroptosis-associated gene signatures, whereas PANC-1 cells exhibited robust co-activation of NRF2 and ATF4, along with induction of unfolded protein response signaling and extensive redox and metabolic remodeling. MSC treatment suppressed TXNIP, a negative regulator of the thioredoxin system, while inducing canonical NRF2 target genes including TXNRD1, NQO1, G6PD, SLC7A11, and GLRX. In MSC-responsive models, pathways linked to iron metabolism and ferroptosis-associated processes were significantly altered, accompanied by changes in iron-handling proteins and lipid peroxidation defenses. Functional assays further demonstrated increased lipid peroxidation and partial rescue of cytotoxicity by ferrostatin-1 and the iron chelator deferoxamine, supporting the involvement of iron-dependent oxidative stress mechanisms. In contrast, HPAF-II cells, characterized by low KYAT1 expression, showed minimal transcriptional engagement and intrinsic resistance to MSC. Collectively, these findings identify KYAT1-dependent metabolic activation and convergence of NRF2-ATF4 stress pathways as key determinants of MSC responsiveness, revealing phenotype-dependent remodeling of redox and ferroptosis-associated networks in PDAC. This work provides a mechanistic framework for exploiting redox vulnerabilities and supports the continued development of selenium-based therapeutic strategies in pancreatic cancer.