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KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP\u2010qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR\u2010433, while dual luciferase assay was carried out to confirm the targeting relationship between miR\u2010433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo\u2010tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A\u2010miR\u2010433\u2010FXYD3\u2010PI3K\u2010AKT axis in the progression of HCC after loss\u2010 and gain\u2010function assays. KDM5A p\u2010p85 and p\u2010AKT were highly expressed but miR\u2010433 was down\u2010regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR\u2010433 by demethylating H3K4me3 on its promoterregion. miR\u2010433 negatively targeted FXYD3. Depleting miR\u2010433 or re\u2010expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down\u2010regulated miR\u2010433 and up\u2010regulated FXYD3\u2010PI3K\u2010AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3\u2010PI3K\u2010AKT axis to enhance angiogenesis in HCC by suppressing miR\u2010433.<\/jats:p>","DOI":"10.1111\/jcmm.16371","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T22:35:26Z","timestamp":1614119726000},"page":"4040-4052","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["KDM5A silencing transcriptionally suppresses the FXYD3\u2010PI3K\/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR\u2010433 up\u2010regulation"],"prefix":"10.1111","volume":"25","author":[{"given":"Yu\u2010Shui","family":"Ma","sequence":"first","affiliation":[{"name":"Central Laboratory for Medical Research Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai China"},{"name":"Department of Radiology The Forth Affiliated Hospital of Anhui Medical University  Hefei China"},{"name":"Cancer Institute Nantong Tumor Hospital  Nantong 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