PROTAC-Surufatinib Suppresses Pancreatic Neuroendocrine Neoplasms Progression by Inducing Ferroptosis through Inhibiting WNT/β-catenin Pathway Mediated by HMOX1

The small-molecule targeting drug Surufatinib is a new strategy for pancreatic neuroendocrine neoplasms (pNENs). However, the adverse reactions of Surufatinib should not be ignored in clinical practice. Based on PROTAC technology, we developed a novel tyrosine kinase (TK) degrader PROTAC-Surufatinib (hereinafter referred to as P-Surufatinib). This study was designed to investigate the effects and underlying mechanism of P-Surufatinib on pNENs. <i>In vitro</i>, we revealed that P-Surufatinib could more effectively inhibit proliferation and angiogenesis, and degrade target proteins in pNENs cells than Surufatinib. The transcriptome sequencing revealed that HMOX1 was the key molecule of P-Surufatinib to inhibit proliferation in pNENs. It was demonstrated that HMOX1 was lowly expressed in pNENs, and P-Surufatinib could up-regulate the expression of HMOX1 in pNENs. Mechanistically, P-Surufatinib inhibited pNENs progression by inducing ferroptosis through the suppression of HMOX1 mediated WNT/β-catenin signaling pathway. <i>In vivo</i>, P-Surufatinib could obviously suppress the growth of subcutaneous tumors in nude mice and enhance the expressional level of HMOX1 in tumorous tissue. In summary, our findings reveal that P-Surufatinib can suppress pNENs progression via inducing ferroptosis through up-regulating the expressional level of HMOX1 by inhibiting WNT/β-catenin signaling pathway, which provides a novel treatment method for pNENs.