Background <p>Advanced clear cell renal cell carcinoma (ccRCC) carries a dismal prognosis, urging the discovery of novel therapeutic targets. Here, we investigate the uncharacterized protein PPP1R18 as a potential driver of ccRCC malignancy.</p> Methods <p>PPP1R18 expression and its prognostic value were evaluated using TCGA, GEO, and CPTAC databases, with validation in clinical samples and cell lines. The biological functions of PPP1R18 were assessed in vitro using siRNA-mediated knockdown in a series of in vitro assays and an in vivo xenograft model. The underlying molecular mechanisms were explored through bioinformatic analysis, Western blotting, and rescue experiments using specific pathway agonists and inhibitors to delineate the signaling cascade.</p> Results <p>PPP1R18 is significantly upregulated in ccRCC and serves as a robust independent predictor of poor survival. Knockdown of PPP1R18 substantially impaired ccRCC cell proliferation, migration, and invasion in vitro and suppressed tumor growth in vivo. Mechanistically, PPP1R18 depletion suppressed the phosphorylation of ERK and inhibited the Wnt/β-catenin pathway, leading to a reversal of the epithelial-mesenchymal transition (EMT) phenotype. Notably, activation of the ERK pathway rescued the inhibitory effects of PPP1R18 knockdown on Wnt/β-catenin signaling and malignant phenotypes. This rescue was subsequently abrogated by a Wnt/β-catenin inhibitor, confirming that Wnt/β-catenin acts downstream of the PPP1R18/ERK axis.</p> Conclusion <p>PPP1R18 is a crucial oncogenic driver and prognostic biomarker in ccRCC. It promotes malignant phenotypes by activating the novel ERK/Wnt/β-catenin signaling axis, offering a potential new target for ccRCC treatment.</p> Graphical abstract <p></p>