A Novel Bruton’s Tyrosine Kinase Inhibitor Suppresses Pancreatic Neuroendocrine Neoplasms Progression via ATF3-Induced Ferroptosis

Objective: Current therapeutic regimens for pancreatic neuroendocrine neoplasms (pNENs) remain limited and fail to yield notable improvements in overall survival. Therefore, the development of novel agents is of paramount importance. Bruton’s tyrosine kinase inhibitors (BTKis) have demonstrated promising therapeutic potential in solid tumors; however, ibrutinib, a classic BTKi, exhibits unsatisfactory clinical efficacy against pNENs. In this study, we synthesized a novel pyrrolopyrimidine-based BTKi, QY21, and aimed to investigate its inhibitory effects on pNEN cell proliferation both in vitro and vivo and identify the core signaling pathways mediating its suppressive effects on pNENs. Methods: CCK-8, EdU, and colony formation assays were conducted to assess the effect of QY21 on pNENs in vitro. Transcriptome sequencing, quantitative real-time PCR, Western blotting, and flow cytometry were employed to explore the mechanisms. A xenograft tumor model in nude mice was established for in vivo validation. Results: QY21 significantly suppressed pNENs proliferation in vitro. Compared with the control and ibrutinib groups, QY21 exhibited stronger tumor growth inhibition in vivo. Histopathological analysis revealed a decreased Ki-67 index in the QY21 group, with no significant organ-toxic lesions observed. Transcriptome sequencing identified ATF3 as the core mediator responsible for the anti-proliferative effect of QY21. ATF3 was poorly expressed in pNENs, while QY21 markedly upregulated ATF3 expression. Mechanistically, QY21 induced ferroptosis by elevating ATF3 levels. The knockdown of ATF3 or administration of ferrostatin-1 significantly attenuated the anti-proliferative capacity of QY21, accompanied by reduced accumulation of reactive oxygen species and lipid peroxidation. Conclusions: This study demonstrates that the novel BTKi QY21 suppresses pNENs proliferation by triggering ATF3-mediated ferroptosis, providing a potential preclinical strategy for pNENs.