Applying this model to wild‐type (WT) and OPN‐deficient (Spp1−/−) animals, we provide evidence for a Janus‐type role of OPN in various states of NASH‐HCC progression eventually resulting in enhanced NAFL, NASH and fibrosis but also more highly differentiated HCC and improved overall survival rate in Spp1−/− mice. The gene discussed is SPP1; the disease is hepatocellular carcinoma.