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Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, and drug resistance severely undermines treatment efficacy. This review summarizes recent advances in elucidating NSCLC drug-resistance mechanisms using multi-omics integration. Multi-omics integration systematically reveals the molecular networks of drug resistance, identifies key biomarkers and targets, and facilitates the screening of high-priority candidates for drug development through experimental validation. Small-molecule inhibitors targeting drug-resistant proteins and multi-omics-guided combination therapies offer strategies to reverse resistance. Future directions involve developing simultaneous multi-omics detection technologies, leveraging artificial intelligence for intelligent data analysis, establishing standardized frameworks for data sharing, and implementing personalized medicine based on multi-omics to improve patient prognosis.<\/jats:p>","DOI":"10.1186\/s41065-025-00570-w","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:02:22Z","timestamp":1769990542000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Multi-omics integration in deciphering non-small cell lung cancer drug resistance: current status, challenges, and future prospects"],"prefix":"10.1186","volume":"163","author":[{"given":"Jidong","family":"Miao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"issue":"7957","key":"570_CR1","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/s41586-023-05776-4","volume":"616","author":"C Abbosh","year":"2023","unstructured":"Abbosh C, Frankell AM. 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