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Despite progress in diagnostic imaging and systemic therapies, early detection and effective targeted interventions remain major clinical challenges. Long non-coding RNAs (lncRNAs), a class of regulatory RNA molecules exceeding 200 nucleotides in length, have emerged as essential regulators of oncogenic signaling, metabolism, and tumor microenvironment in HCC. This review provides a comprehensive overview of the molecular mechanisms, biological functions, and clinical relevance of key lncRNAs involved in HCC progression. We summarize the dual roles of lncRNAs as oncogenic drivers and tumor suppressors, with particular emphasis on oncogenic lncRNAs including CYTOR, UCA1, MALAT1, SPRY4-IT1, uc001ncr, AF085935, HULC, and HOTAIR. Their regulatory functions are discussed within major cancer-associated signaling networks, including the PI3K\/AKT\/mTOR, Wnt\/\u03b2-catenin, TGF-\u03b2\/NF-\u03baB, and EMT-associated pathways. Furthermore, each lncRNA is discussed in the context of its expression pattern, endogenous RNA (ceRNA) interactions, molecular partners, and functional contributions to cellular proliferation, invasion, metastasis, angiogenesis, immune modulation, and therapeutic resistance. In addition, we explore the emerging potential of lncRNAs as minimally invasive diagnostic and prognostic biomarkers, owing to their stability and detectability in tissue and circulating biofluids. We also discuss recent advances in RNA- targeted therapeutic strategies, including RNA interference, siRNA-mediated silencing, antisense oligonucleotides, and CRISPR-based genome editing approaches. Collectively, this review highlights the importance of integrating lncRNA expression signatures into personalized HCC management and the promising role of lncRNA-based diagnostics and therapeutics in transforming the future landscape of liver cancer detection, prognosis, and treatment.<\/jats:p>","DOI":"10.1186\/s43046-026-00380-9","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T06:38:58Z","timestamp":1782715138000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding the functional landscape of long non-coding RNAs in hepatocellular carcinoma: molecular mechanisms, clinical implications, and therapeutic prospects"],"prefix":"10.1186","volume":"38","author":[{"given":"Humera","family":"Naveed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zain-Ul","family":"Abidien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaleem","family":"Maqsood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iram","family":"Amin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Shahid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3298-5735","authenticated-orcid":false,"given":"Samia","family":"Afzal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"issue":"1","key":"380_CR1","doi-asserted-by":"publisher","first-page":"e18761429310703","DOI":"10.2174\/0118761429310703240823045808","volume":"17","author":"B Sensi","year":"2024","unstructured":"Sensi B, et al. 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