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This investigation reveals the pivotal involvement of calcium\u2010sensing receptor (CaSR) in HCC advancement and its potential as a promising therapeutic target. Through pharmacological blockade with NPS\u20102143 and genetic knockdown using siRNA, we found that CaSR inhibition substantially reduced HCC cell proliferation, migration, and invasion, while promoting apoptotic cell death in HepG2 and SMMC\u20107721 cells. At the molecular level, CaSR interference triggered p38 MAPK activation, while inhibiting the ERK1\/2 cascade, resulting in diminished expression of proliferation indicators (PCNA), metastatic markers (MMP\u20102\/9), and cell survival proteins (Bcl\u20102), concurrent with elevated levels of apoptosis mediators (Bax, cleaved caspase\u20103). In\u00a0vivo, NPS\u20102143 significantly suppressed xenograft tumour growth. Western blotting of xenograft tumour tissues further showed increased p\u2010p38\/p38 and Bax levels and decreased p\u2010ERK\/ERK, MMP\u20109, and Bcl\u20102 levels, consistent with the in\u00a0vitro findings. Additional validation in a male nude mouse xenograft model using Huh7 cells further supported the anti\u2010tumour effect of NPS\u20102143 in another independent HCC model. These findings suggest that CaSR facilitates malignant HCC cebehaviours through MAPK signalling and may represent a potential therapeutic target for HCC treatment.<\/jats:p>","DOI":"10.1111\/jcmm.71389","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:16:29Z","timestamp":1790741789000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of Calcium\u2010Sensing Receptor Suppresses Malignant Behaviours of Human Hepatocellular Carcinoma"],"prefix":"10.1111","volume":"30","author":[{"given":"Tingting","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Science and Technology Talents Affiliated Kunshan Hospital of Jiangsu University  Kunshan Jiangsu China"},{"name":"Department of Preventive Medicine and Public Health Laboratory Sciences, School of Basic Medicine and Public Health Jiangsu University  Zhenjiang Jiangsu 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