HMGCS1 as a Potential Mediator of Resistance to EZH2 Inhibition via Ferroptosis mediated by PI3K/AKT/mTOR Pathway in the Pancreatic Neuroendocrine Neoplasms

In recent years, EZH2 inhibitors have showed potential therapeutic value in certain hematological malignancies and solid tumors. However, the role and mechanisms of EZH2 in pancreatic neuroendocrine neoplasms (pNENs) remain unclear. This study investigated the effects and mechanism of the EZH2 inhibitor GSK126 on pNENs. Public database analysis revealed that increased EZH2 expression correlates with poor prognosis in pNENs patients. We found that EZH2 is significantly upregulated in pNENs tissues and cell lines, and its knockdown or treatment with GSK126 inhibits proliferation and induces ferroptosis in vitro. In vivo, EZH2 knockdown or GSK126 treatment suppressed subcutaneous tumor growth in nude mice. Mechanistic studies showed that GSK126 induces ferroptosis by inhibiting the PI3K/AKT/mTOR pathway. Additionally, GSK126 upregulated HMGCS1, a gene linked to ferroptosis. HMGCS1 may act as an oncogene by activating the PI3K/AKT/mTOR pathway and knockdown of HMGCS1 can enhance GSK126-induced ferroptosis and the inhibitory effect of GSK126 on the PI3K/AKT/mTOR pathway. Furthermore, combining GSK126 with everolimus, an mTOR inhibitor used clinically for pNENs, more effectively inhibited cell proliferation and tumor growth. In summary, Our findings reveal that the EZH2 inhibitor GSK126 induces ferroptosis by inhibiting the PI3K/AKT/mTOR pathway, suppressing pNENs progression, and HMGCS1 may mediate resistance to EZH2 inhibitors, offering new insights into pNENs treatment.