IDH2-siRNA nanoparticles induce apoptosis in HeLa cell by regulating the miR204/mitophagy pathway

Purpose Mitochondrial dysfunction plays an important role in modulation of cancer and considered as a therapeutic target for anticancer treatment. Mutation of mitochondrial protein isocitrate dehydrogenase 2 (IDH2) has been identified in various cancers. However, the role of wild-type IDH2 in cancer proliferation and migration, particularly in cervical cancer, remains poorly understood. Methods In the present study, we examined the antitumor mechanism of IDH2 deficiency in HeLa cervical cancer cells using both in vitro assay and in vivo xenograft mouse model. Poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles encapsulating IDH2-specific siRNA (siIDH2-NP) were used IDH2 downregulation. Results IDH2 siRNA. IDH2 deficiency suppressed cell proliferation, migration, as well as mitochondrial homeostasis in HeLa cells. IDH2 deficiency markedly inhibited cell proliferation and migration while disrupting mitochondrial homeostasis in HeLa cells. The mitochondrial dysfunction led to the upregulation of endoplasmic reticulum (ER) stress and mitochondrial unfolded protein response (UPRmt) markers, accompanied by a significant reduction in PINK1 accumulation and impaired Parkin translocation to mitochondria suppressing mitophagy. Additionally, STAT3 de-phosphorylation in IDH2 deficient cells increased miR204 expression, which inhibited PINK1 expression and suppressed mitophagy. Consistent findings were obtained in vivo , with significantly reduced tumor volume in treatment of siIDH2-NP. Conclusions These findings suggest that IDH2 deficiency induces apoptotic cell death by disrupting mitochondrial homeostasis and suppressing mitophagy. This study highlights IDH2 as a potential therapeutic target and miR204 as a novel mediator in cervical cancer, providing a promising avenue for the development of anticancer strategies.