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ABSTRACT Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation

of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we

designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells.

STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the

tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively

sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools

capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CSF3R-AS PROMOTES HEPATOCELLULAR CARCINOMA PROGRESSION AND SORAFENIB RESISTANCE THROUGH THE CSF3R/JAK2/STAT3 POSITIVE FEEDBACK

LOOP Article Open access 28 March 2025 CIRCRNA-SORE MEDIATES SORAFENIB RESISTANCE IN HEPATOCELLULAR CARCINOMA BY STABILIZING YBX1 Article Open access 26 December 2020 SHC3 PROMOTES

HEPATOCELLULAR CARCINOMA STEMNESS AND DRUG RESISTANCE BY INTERACTING WITH Β-CATENIN TO INHIBIT ITS UBIQUITIN DEGRADATION PATHWAY Article Open access 15 March 2021 DATA AVAILABILITY The

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ACKNOWLEDGEMENTS This work was supported by the National Natural Science Foundation of China (22077144, 81973359), Guangdong Basic and Applied Basic Research Foundation (2022A1515012204),

Joint Foundation of Guangdong and Macau for Science and Technology Innovation (2022A0505020024), the Science and Technology Development Fund, Macau SAR (File No. 0053-2021-AGJ). The Key

Research and Development Plan of Guangzhou City (202206080007) and Guangdong Provincial Key Laboratory of Construction Foundation (2023B1212060022) are also appreciated. AUTHOR INFORMATION

Author notes * These authors contributed equally: Qi-yi Zhang, Wen Ding. AUTHORS AND AFFILIATIONS * National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation,

Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China Qi-yi Zhang, Wen Ding, Jian-shan Mo, 

Shu-min Ou-yang, Zi-you Lin, Ke-ren Peng, Jin-ping Lei & Xiao-lei Zhang * State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060,

China Guo-pin Liu & Yan-dong Wang * State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China Jin-jian Lu *

Department of Medicine, Division of Hematology-Oncology, and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA Pei-bin Yue Authors *

Qi-yi Zhang View author publications You can also search for this author inPubMed Google Scholar * Wen Ding View author publications You can also search for this author inPubMed Google

Scholar * Jian-shan Mo View author publications You can also search for this author inPubMed Google Scholar * Shu-min Ou-yang View author publications You can also search for this author

inPubMed Google Scholar * Zi-you Lin View author publications You can also search for this author inPubMed Google Scholar * Ke-ren Peng View author publications You can also search for this

author inPubMed Google Scholar * Guo-pin Liu View author publications You can also search for this author inPubMed Google Scholar * Jin-jian Lu View author publications You can also search

for this author inPubMed Google Scholar * Pei-bin Yue View author publications You can also search for this author inPubMed Google Scholar * Jin-ping Lei View author publications You can

also search for this author inPubMed Google Scholar * Yan-dong Wang View author publications You can also search for this author inPubMed Google Scholar * Xiao-lei Zhang View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS QYZ and WD: Conception, formal analysis, investigation, write original draft. JSM: Resources,

investigation, methodology. SMOY, ZYL, KRP, and GPL: Data curation, investigation, methodology. PBY, JJL, and JPL: Methodology, writing–review and editing. XLZ, and YDW: Conceptualization,

design, supervision, funding acquisition, writing–review and editing. CORRESPONDING AUTHORS Correspondence to Yan-dong Wang or Xiao-lei Zhang. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION WB FIGURES ORIGNIAL RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g. a society or

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this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Zhang, Qy., Ding, W., Mo, Js. _et

al._ Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma. _Acta Pharmacol Sin_ 45, 1701–1714 (2024).

https://doi.org/10.1038/s41401-024-01261-4 Download citation * Received: 17 November 2023 * Accepted: 03 March 2024 * Published: 12 April 2024 * Issue Date: August 2024 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * STAT3 * antisense oligonucleotide * hepatocellular

carcinoma * acquired sorafenib-resistance