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Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases and has a 5-year survival rate of ~19%. Since more than half of NSCLC patients present with metastatic disease at the time of diagnosis, early diagnosis is crucial for providing patients with the most effective treatment strategy. This study integrated transcriptome data between cancer and adjacent tissues from GEO and TCGA databases through bioinformatics analysis, and screened zinc finger CCCH-type containing 15 (ZC3H15) as a key differentially expressed gene in NSCLC. ZC3H15 expression levels were found to be significantly higher in NSCLC tissue than normal tissue and correlated with tumor size, TNM stage, lymph node metastasis and poor prognosis of patients. Overexpression of ZC3H15 promoted the proliferation, migration and invasion of NSCLC cells through activation of the AKT-mTOR signaling pathway. To elucidate the underlying molecular mechanism, we determined that ZC3H15 could bind to PTEN through its DFRP structural domain and recruited the E3 ligase TRIM56 to promote PTEN ubiquitination. In addition, overexpression of ZC3H15 increased the resistance of NSCLC cells to cisplatin. Therefore, ZC3H15 promotes the malignant phenotype of NSCLC through recruitment of TRIM56 to ubiquitinate PTEN, decreasing its expression and driving increased AKT-mTOR signaling pathway and cisplatin resistance. These findings provide a scientific basis for the development of targeted therapies against ZC3H15, which may lead to new therapeutic strategies for NSCLC patients.<\/jats:p>","DOI":"10.1038\/s41419-025-08138-2","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T14:41:52Z","timestamp":1767969712000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["ZC3H15 regulates the ubiquitination of PTEN via recruitment of TRIM56 and promotes malignant progression of non-small cell lung cancer"],"prefix":"10.1038","volume":"17","author":[{"given":"Peihong","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peifeng","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0183-144X","authenticated-orcid":false,"given":"Mingfang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9449-281X","authenticated-orcid":false,"given":"Ming","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"8138_CR1","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/S0140-6736(21)00312-3","volume":"398","author":"AA Thai","year":"2021","unstructured":"Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. 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All animal experiments were approved by the Institutional Animal Care and Use Committee of China Medical University and adhered to the guidelines for the care and use of laboratory animals issued by the China Animal Research Council(No.[2024]369 and KT2024430).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"17"}}