Chemoresistance is still a critical challenge for efficient treatment of multiple myeloma (MM) during the bortezomib-based chemotherapy. Recent studies have suggested that heme oxygenase-1 (HO-1) is involved in apoptosis, proliferation and chemoresistance in cancer cells. Here we aim to investigate the role and mechanism of HO-1 in bortezomib-sensitivity to myeloma cells. In the study population, we found that HO-1 was highly expressed in CD138 + primary myeloma cells, which was positively associated with Gas6 expression and Gas6 plasma levels in MM patients. Downregulation of HO-1 using pharmacological inhibitor ZnPPIX or siRNA knockdown significantly enhanced myeloma cell sensitivity to bortezomib in human primary CD138 + cells, U266 and RPMI8226 cell lines. Mechanistically, HO-1 regulated Gas6 production via ERK/STAT3 axis. Combination with HO-1 inhibition increased bortezomib-induced apoptosis and antiproliferative effects via suppressing Gas6 production. These findings suggest that combination of bortezomib and HO-1 inhibitor may serve as a promising therapeutic target against bortezomib-resistant MM. www.aging-us.com 6612 AGING with chemoresistance [13]. However, the underlying mechanisms between HO-1 and chemoresistance remain unclear. Growth arrest-specific gene 6 (Gas6) is a 75 kDa secreted protein containing an N-terminal gamma-carboxyglutamic acid domain [14]. Gas6 has been implicated in promoting proliferation, migration and survival of multiple types of cancer cells, including breast, melanoma, ovarian, renal and prostate cancers [15-19]. Besides, emerging evidence indicate that high expression of Gas6 is associated with a poor prognosis in hematologic malignancies. Patients with acute myeloid leukemia expressing Gas6, especially those aged ≥60 years, more often fail to achieve a complete remission and have shorter disease-free and overall survive than those without Gas6 expression [20]. In addition, aberrant Gas6 secretion promotes acute myeloid leukemia cells growth and chemoresistance [21]. It suggests that Gas6 represents a critical factor for chemoresistance. However, whether HO-1 mediates the sensitivity of MM to bortezomib via Gas6 is still unknown and remains to be investigated. We hypothesized that HO-1 inhibition downregulates Gas6 to overcome adaptive bortezomib resistance in MM, providing a potential target against drug resistance in the treatment of MM. Additionally, we aimed at investigating the molecular mechanism how HO-1 regulates Gas6 in bortezomib-resistant myeloma cells. RESULTS High HO-1 expression is associated with increased Gas6 expression in patients with MM