In the present study, we revealed the following findings: 1) in human MM cell lines, including U266 and RPMI8226, HO-1 contributed to upregulate Gas6 expression and secretion; 2) inhibition of HO-1 downregulated Gas6 expression and secretion, and subsequently overcame bortezomib resistance in MM cells; 3) the addition of exogenous Gas6 abolished the effects enhanced by HO-1, and this phenotype could be reversed by Gas6 neutralizing antibody. This evidence concerns the gene HMOX1 and Miyoshi myopathy.