{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T10:40:59Z","timestamp":1772102459618,"version":"3.50.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Despite significant advances in understanding the occurrence, progression and treatment of chronic lymphocytic leukemia (CLL), there remains a need to explore novel mechanisms and therapeutic strategies. In this study, we discovered that hepatocyte growth factor (HGF), a cytokine highly expressed by bone marrow mesenchymal stem cells within the microenvironment, activates the AKT, ERK and STAT3 signaling pathways, promotes the expression of anti-apoptotic proteins BCL-2, MCL-1, and BCL-xL, thereby enhancing CLL cell survival and resistance to both natural and ABT-199-induced apoptosis. Knockdown of c-MET, the unique receptor for HGF, using lentivirus-mediated shRNA, significantly attenuated the activation of these pro-survival signaling pathways and downregulated the expression of anti-apoptotic proteins in the BCL-2 family. Consequently, this inhibited CLL cell proliferation and promoted apoptosis. Similarly, pharmacological targeting of the HGF\/c-MET pathway with the inhibitor capmatinib markedly suppressed the activation of pro-survival signaling pathways, reduced the expression of anti-apoptotic proteins, inhibited cell proliferation, arrested cell cycle at G0\/G1 stage, induced apoptosis, and enhanced the pro-apoptotic effect of ABT-199. In summary, this study highlights the critical role of HGF\/c-MET axis in CLL cell survival and demonstrates that targeting this pathway holds therapeutic potential for the treatment of CLL.<\/jats:p>","DOI":"10.3389\/fphar.2025.1612916","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:44:43Z","timestamp":1748583883000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["HGF\/c-MET axis contributes to CLL cell survival by regulating multiple mechanisms making it a potential therapeutic target for CLL treatment"],"prefix":"10.3389","volume":"16","author":[{"given":"Shihao","family":"Liang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoya","family":"Shao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueqiong","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuanyue","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Binghui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guomin","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiping","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1007\/s00277-017-2980-3","article-title":"Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed\/refractory multiple myeloma","volume":"96","author":"Baljevic","year":"2017","journal-title":"Ann. 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