SLFN11 Enhances PARPi Sensitivity in Ovarian Cancer via Ubiquitin-Mediated Stabilization

Schlafen family member 11 (<i>SLFN11</i>), implicated in cancer drug resistance, may improve poly(ADP-ribose) polymerase inhibitor (PARPi) efficacy. This study investigates <i>SLFN11</i>'s role in epithelial ovarian cancer (EOC) progression and its influence on PARPi sensitivity, particularly in <i>BRCA</i>-wild-type contexts, with a focus on its emerging function in proteostasis regulation. <i>SLFN11</i> expression in EOC and adjacent tissues was evaluated via immunohistochemistry, quantitative polymerase chain reaction (PCR), and Western blot. Functional assays-including cell viability, transwell migration, wound healing, and colony formation-assessed <i>SLFN11</i>'s effects on SKOV3 cells (<i>BRCA</i>-wild-type) proliferation and invasiveness. PARPi sensitivity in SKOV3 cells with <i>SLFN11</i> knockdown or overexpression (OE) was tested using Cell Counting Kit (CCK)-8 and Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assays. Protein stability and ubiquitination levels of <i>PARP1/2</i> were analyzed as the central mechanism. <i>SLFN11</i> mRNA and protein levels were markedly lower in EOC tissues compared with normal tissues. Silencing <i>SLFN11</i> enhanced EOC cell proliferation, migration, and invasion, whereas OE inhibited these malignant behaviors. <i>SLFN11</i> knockdown reduced PARPi-induced apoptosis and drug sensitivity, while its OE amplified these responses. Mechanistically, we demonstrate that <i>SLFN11</i> suppresses global proteotoxic ubiquitination, thereby specifically stabilizing PARP1/2 proteins and potentiating PARPi-mediated DNA damage through enhanced chromatin trapping. <i>SLFN11</i> enhances PARPi sensitivity in EOC by stabilizing PARP1/2 via inhibition of proteotoxic ubiquitination, supporting its role as a biomarker in a <i>BRCA</i>-wild-type EOC cell model where PARPi efficacy is limited by intrinsic resistance. While the application of PARPi in other subtypes of EOC still requires further validation, <i>SLFN11</i> may improve PARPi response and could be explored as a strategy to address PARPi resistance.