Stojanovic, LoraAbbotts, RachelTripathi, KaushlendraCoon, Collin M.Rajendran, SaranyaFarid, Elnaz AbbasiHostetter, GalenGuarnieri, Joseph W.Wallace, Douglas C.Liu, ShengWan, JunCalendo, GennaroMarker, RebeccaGohari, ZahraInayatullah, Mohammed M. A.Tiwari, Vijay K.Kader, TanjinaSantagata, SandroDrapkin, RonnyKommoss, StefanPfisterer, JacobusKonecny, Gottfried E.Coopergard, RyanIssa, Jean-PierreWinterhoff, Boris J. N.Topper, Michael J.Sandusky, George E.Miller, Kathy D.Baylin, Stephen B.Nephew, Kenneth P.Rassool, Feyruz V.2024-12-062024-12-062024-10-21Stojanovic L, Abbotts R, Tripathi K, et al. ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer. Preprint. bioRxiv. 2024;2024.10.18.618659. Published 2024 Oct 21. doi:10.1101/2024.10.18.618659https://hdl.handle.net/1805/44797DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR. In patient OC databases, high ZNFX1 expression levels correlate with advanced stage disease. ZNFX1 expression alone significantly correlates with an increase in overall survival in a phase 3 trial for therapy-resistant OC patients receiving bevacizumab in combination with chemotherapy. In correlative RNA-seq data, inflammasome signaling through ZNFX1 correlates with abnormal vasculogenesis. ZNFX1 controls PMR signaling through the mitochondria and may serve as a biomarker to facilitate offering personalized therapy in OC patients, highlighting the strong translational significance of our findings.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalDNA damageSTINGZNFX1InflammasomeInterferonMitochondriaOvarian cancerReactive oxygen speciesTumor suppressorViral mimicryArticle