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Dual-specificity phosphatases (DUSPs) catalyze the dephosphorylation of tyrosine and serine/threonine residues in target proteins. Atypical DUSPs (aDUSPs) lack substrate-binding motifs, suggesting their potential to target a diverse array of substrates. This study demonstrated that DUSP21, an aDUSP, is induced by leukemia inhibitory factor (LIF) in HeLa cells and acts as a negative regulator of LIF-induced signal transducer and activator of transcription 3 (STAT3) activation. Overexpressed DUSP21 co-localized and interacted with STAT3 in HeLa cells. Recombinant DUSP21 directly dephosphorylated STAT3 in vitro. Additionally, DUSP21 overexpression modulated STAT3-dependent growth of Ba/F3-G133 cells. These findings indicate that LIF-induced DUSP21 exerts an inhibitory effect on the LIF/STAT3 signaling pathway, thereby functioning as a suppressor of STAT3-mediated transcriptional activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)