Niraparib promotes ferroptosis by inhibiting TM4SF1 expression through ALKBH1-mediated 6mA modification in BRCA...

Niraparib significantly improves the prognosis of patients with BRCA wild-type ovarian cancer (BRCAwt OC). However, the underlying mechanisms remain elusive. N6-methyladenine DNA (6mA) modification has emerged as a critical epigenetic regulator in cancer progression. We investigated whether niraparib exerts antitumor effects by modulating 6mA modification in BRCAwt OC models.

The 6mA modification levels were assessed using dot blot, ELISA, and 6mA-IP-seq. The regulatory role of ALKBH1 in transmembrane 4 L six family member 1 (TM4SF1) mRNA expression and 6mA modification was examined via RT-qPCR, Western blot, and 6mA-IP-qPCR, respectively. Using the CCK-8 assay, colony formation assay, wound healing assay, Transwell assay, and subcutaneous tumor xenograft models, the function of TM4SF1 in tumor growth was evaluated in vivo and in vitro. Additionally, the association between TM4SF1 expression and ferroptosis was assessed by measuring Fe²⁺ and lipid reactive oxygen species (ROS) levels using a transmission electron microscope (TEM).

Our findings demonstrated that niraparib treatment significantly reduced the expression of TM4SF1 by increasing ALKBH1-mediated 6mA modification. Mechanistically, niraparib increases the expression of ALKBH1, which binds to the TM4SF1 promoter, thereby regulating its 6mA modification and suppressing its expression. Furthermore, TM4SF1 knockdown reduced cell proliferation, invasion, and migration, along with tumor growth in vivo and in vitro. Inhibition of TM4SF1 enhanced Fe²⁺ accumulation and lipid ROS production, leading to the induction of ferroptosis.

Niraparib exhibits antitumor effects and promotes ferroptosis by inhibiting TM4SF1 expression through ALKBH1-mediated 6mA modification in BRCAwt OC. These findings emphasize the potential application of niraparib in BRCAwt OC and reveal the important role of epigenetic regulation in cancer treatment.