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In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>4\u2010PBA was administered alone or in combination with diethylnitrosamine to investigate its long\u2010term effect on liver tumorigenesis. The role of 4\u2010PBA in oncogene\u2010induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co\u2010expressed with hMet and \u03b2\u2010catenin point mutation (S45Y) was also observed. RNA\u2010seq and PCR array were used to screen the pathways and genes involved. <jats:italic>In vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> studies were conducted to explore the effect of 4\u2010PBA on liver and validate the underlying mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>4\u2010PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b\u2010Fzd5 mediating \u03b2\u2010catenin signaling. Peroxisome proliferator\u2010activated receptors (PPAR)\u2010\u03b1\u00a0induced by 4\u2010PBA was responsible for the activation of \u03b2\u2010catenin signaling. Thus, intervention of PPAR\u2010\u03b1 reversed 4\u2010PBA\u2010induced initiation of LCSCs and HCC development <jats:italic>in vivo<\/jats:italic>. Further study revealed that 4\u2010PBA could not only upregulate the expression of PPAR\u2010\u03b1\u00a0transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR\u2010\u03b1\u00a0expression predicted poor prognosis in HCC patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>4\u2010PBA could upregulate PPAR\u2010\u03b1 to initiate LCSCs by activating \u03b2\u2010catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor\u2010promoting effect of 4\u2010PBA under HCC\u2010inducing environment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.379","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T08:10:02Z","timestamp":1619856602000},"source":"Crossref","is-referenced-by-count":47,"title":["4\u2010phenylbutyric acid promotes hepatocellular carcinoma via initiating cancer stem cells through activation of PPAR\u2010\u03b1"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8957-9404","authenticated-orcid":false,"given":"Shu\u2010Zhen","family":"Chen","sequence":"first","affiliation":[{"name":"National Center for Liver Cancer Second Military Medical University  Shanghai China"},{"name":"International Cooperation Laboratory on Signal Transduction Eastern Hepatobiliary Surgery Hospital Second Military Medical University  Shanghai 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