Background <p>High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy marked by widespread metastasis, most notably to the omentum. However, the molecular mechanisms driving this process remain poorly understood.</p> Methods <p>We present an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from normal ovaries, primary tumors, and omental metastases to generate a high-resolution cellular landscape of HGSOC. LAPTM5 expression was examined by immunohistochemistry, immunofluorescence, qPCR, western blotting, and analyses of TCGA datasets. Functional assays including Transwell migration/invasion, wound healing, flow cytometry, single-nucleotide variant (SNV) and alternative splicing (AS) analysis were performed after LAPTM5 knockdown. The proteins expression involved in epithelial-mesenchymal transition (EMT) and TGF-β mediated signaling pathways was verified by qPCR and western blotting. The critical role of LAPTM5 on metastasis in vivo was detected by the tumor-bearing mice model.</p> Results <p>We identified a metastasis-associated epithelial subcluster characterized by immune suppression and poor prognosis, with <i>LAPTM5</i> emerging as a defining marker. Functional assays revealed that <i>LAPTM5</i> silencing significantly impaired HGSOC cell migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and reduced metastatic burden in vivo. Mechanistically, LAPTM5 activates the TGF-β/Smad signaling pathway, promoting EMT and facilitating omental metastasis. Intriguingly, <i>LAPTM5</i> knockdown led to reduced single-nucleotide variant (SNV) accumulation and alternative splicing (AS) events, thereby decreasing the expression of metastasis-associated genes.</p> Conclusions <p>These findings identify <i>LAPTM5</i> as a key regulator of TGF-β/Smad-driven epithelial plasticity and omental dissemination in HGSOC, positioning it as both a prognostic biomarker and a potential therapeutic target for advanced-stage disease.</p>