Quercetin ameliorates imatinib-induced ovarian damage by regulating mitochondrial dysfunction and PANoptosis via the...

Imatinib (IMA), a front-line targeted therapy, was demonstrated by our prior study to potentially cause premature ovarian insufficiency (POI) after long-term administration. Additionally, we found that quercetin (QUE) may ameliorate IMA-induced ovarian injury by regulating mitophagy. Previous studies have shown that mitochondrial dysfunction may be involved in various cell death pathways. PANoptosis is a recently identified form of cell death that exhibits characteristics of pyroptosis, apoptosis, and necroptosis simultaneously. The present study further investigates whether IMA induces PANoptosis via mitochondrial dysfunction and explores the underlying mechanisms and potential therapeutic targets. In vitro experiments on granulosa cells revealed that IMA induced PANoptosis, characterized by membrane blebbing and swelling, pyknosis, as well as rupture of the nuclear and plasma membranes observed via transmission electron microscopy and confocal microscopy. This was accompanied by increased lactate dehydrogenase release, an elevated proportion of propidium iodide positive cells, and activation of caspase-3 (apoptosis), gasdermin D (GSDMD, pyroptosis), and mixed lineage kinase domain-like protein (MLKL, necroptosis). Network pharmacology revealed that the related genes associated with IMA, QUE, mitochondrial function, and POI were enriched in the MAPK pathway, with RAF1 identified as a key target. Western blot analysis demonstrated that IMA upregulated phosphorylation of RAF1, its downstream effector ERK1/2, and the mitochondrial fission mediator Drp1 (Ser616) in granulosa cells and ovarian. GW5074 (a RAF1 inhibitor), Mdivi1 (a Drp1 inhibitor), and QUE restored mitochondrial membrane potential and mitochondrial superoxide levels in granulosa cells and oocytes, suppressed IMA-induced PANoptosis, and improved granulosa cell viability and oocyte quality. These findings provide new insights into potential strategies for protecting ovarian function during IMA treatment.