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However, little is known about how periostin regulates both hepatic fibrosis and tumor growth in the progression of HCC. Here we demonstrate that periostin deficiency impairs HCC development and decreases tissue stiffness of liver tumors in DEN\/CCl<jats:sub>4<\/jats:sub>\u2010treated mice. Increased matrix stiffness enhanced periostin expression in hepatic stellate cells (HSCs). The combination of periostin and increased stiffness synergistically promoted HCC cell proliferation <jats:italic>in vitro<\/jats:italic>. Moreover, periostin deficiency in HSCs impaired both HSC\u2010promoted and stiffness\u2010increased HCC cell proliferation <jats:italic>in vivo<\/jats:italic>. We further demonstrated that periostin promotes Indian hedgehog (IHH) expression in HCC cells through the integrin\u2010PYK2\u2010TAZ pathway. Conversely, IHH increased the expression of periostin in HSCs via GLI2. Periostin expression positively correlates with fibrotic features and IHH signaling in clinical HCC tissues. Collectively, these findings indicate that periostin and IHH cooperatively contribute to the development of HCC by regulating the tumor\u2013stroma crosstalk via the periostin\u2010integrin\u2010PYK2\u2010TAZ\u2010IHH pathway in tumor cells and IHH\u2010GLI2\u2010periostin signaling in HSCs. \u00a9 2025 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6467","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T05:22:56Z","timestamp":1757654576000},"page":"275-288","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Periostin\u2010<scp>IHH<\/scp> feedforward loop promotes hepatocellular carcinoma development by enhancing hepatic fibrosis and tumor cell proliferation"],"prefix":"10.1002","volume":"267","author":[{"given":"Bin","family":"Liu","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital, State Key Laboratory of Cellular 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