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Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating the sensitivity of tumor cells to various chemotherapeutics including sorafenib. However, the underlying mechanisms are very complex and are not fully elucidated. By comparing the transcriptome sequencing data of sorafenib\u2010sensitive and \u2010insensitive HCC patients, it is revealed that cofilin 1 (CFL1) is highly expressed in the tumor tissues of sorafenib\u2010insensitive HCC patients and closely correlated with their poor prognosis. Mechanically, CFL1 can promote phosphoglycerate dehydrogenase transcription and enhance serine synthesis and metabolism to accelerate the production of antioxidants for scavenging the excessive reactive oxygen species induced by sorafenib, thereby impairing the sorafenib sensitivity of HCC. To translate this finding and consider the severe side effects of sorafenib, a reduction\u2010responsive nanoplatform for systemic co\u2010delivery of CFL1 siRNA (siCFL1) and sorafenib is further developed, and its high efficacy in inhibiting HCC tumor growth without apparent toxicity is demonstrated. These results indicate that nanoparticles\u2010mediated co\u2010delivery of siCFL1 and sorafenib can be a new strategy for the treatment of advanced HCC.<\/jats:p>","DOI":"10.1002\/advs.202207118","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T02:16:16Z","timestamp":1684462576000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)\u2010Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib"],"prefix":"10.1002","volume":"10","author":[{"given":"Senlin","family":"Li","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong\u2010Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou 510120 P. R. 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