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However, no drug is available to target NAFLD\u2010HCC. In this study, we aim to unravel novel therapeutic targets of NAFLD\u2010HCC utilizing a high\u2010throughput CRISPR\/Cas9 screening strategy. We utilized the Epi\u2010drug CRISPR\/Cas9 library consisting of single\u2010guide RNAs (sgRNAs) targeting over 1,000 genes representing the FDA\u2010approved drug targets and epigenetic regulators to perform loss\u2010of\u2010function screening in two NAFLD\u2010HCC cell lines (HKCI2 and HKCI10). CRISPR\/Cas9 library screening unraveled\n                    <jats:italic>TUBB4B<\/jats:italic>\n                    as an essential gene for NAFLD\u2010HCC cell growth. TUBB4B was overexpressed in NAFLD\u2010HCC tumors compared with adjacent normal tissues (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200917) and was associated with poor survival (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). RNA\u2010sequencing and functional assays revealed that TUBB4B knockout in NAFLD\u2010HCC promoted cell apoptosis, cell cycle arrest, and cellular senescence, leading to suppressed NAFLD\u2010HCC growth\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . We identified that TUBB4B inhibitor mebendazole (MBZ), an FDA\u2010approved drug, inhibited NAFLD\u2010HCC growth by inducing apoptosis and cellular senescence. Since protein expression of pro\u2010survival Bcl\u2010xL was induced in TUBB4B knockout NAFLD\u2010HCC cells, we examined combination of TUBB4B inhibition with navitoclax, a Bcl\u2010xL inhibitor that selectively targets senescent cells. Consistent with our hypothesis, either TUBB4B knockout or MBZ synergized with navitoclax to inhibit NAFLD\u2010HCC cell growth via the induction of intrinsic and extrinsic apoptosis pathways. In summary, TUBB4B is a novel therapeutic target in NAFLD\u2010HCC. Inhibition of TUBB4B with MBZ in combination with navitoclax synergistically inhibited NAFLD\u2010HCC cell growth, representing a promising strategy for the treatment of NAFLD\u2010HCC. \u00a9 2023 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6065","type":"journal-article","created":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T10:29:12Z","timestamp":1676370552000},"page":"71-83","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["<scp>TUBB4B<\/scp>\n                    is a novel therapeutic target in non\u2010alcoholic fatty liver disease\u2010associated hepatocellular carcinoma"],"prefix":"10.1002","volume":"260","author":[{"given":"Zhenjie","family":"Yang","sequence":"first","affiliation":[{"name":"Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease Li Ka Shing Institute of Health Sciences, CUHK\u2010Shenzhen Research Institute, The Chinese University of Hong Kong  Hong Kong SAR PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease Li Ka Shing Institute of Health Sciences, CUHK\u2010Shenzhen Research Institute, The Chinese University of Hong Kong  Hong Kong SAR PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi Chun","family":"Wong","sequence":"additional","affiliation":[{"name":"Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease Li Ka Shing Institute of Health Sciences, CUHK\u2010Shenzhen Research Institute, The Chinese University of Hong Kong  Hong Kong SAR PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixin","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease Li Ka Shing Institute of Health Sciences, CUHK\u2010Shenzhen Research Institute, The Chinese University of Hong Kong  Hong Kong SAR PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huarong","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease Li Ka Shing Institute of Health Sciences, CUHK\u2010Shenzhen Research Institute, The Chinese University of Hong Kong  Hong Kong SAR PR 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