<p>Early apoptosis of grafted islets is one of the critical challenges that significantly impact the efficacy of islet transplantation. We employed Staurosporine to pre-induce apoptosis in bone marrow mesenchymal stem cells (BMSCs). The conditioned medium from apoptotic BMSCs was then used to pretreat β cells, which notably enhanced the suppression of β cell apoptosis. For in vivo experiments, co-transplantation of islets and apoptotic BMSCs under the renal capsule of diabetic rats inhibited islets apoptosis and resulted in better transplantation outcomes. Subsequently proteomic analysis revealed that the iron-loaded form of Lcn2 protein (holo-Lcn2) secreted by apoptotic BMSCs played a crucial role in exerting anti-apoptotic effects. Holo-Lcn2 binds to the Slc22a17 transporter on cell membrane, facilitating the transport of Fe³⁺ into cells. Inhibition of Fe³⁺ transport suppressed the anti-apoptotic effect of holo-Lcn2. Thus, we hypothesize that apoptotic BMSCs reduce grafted islets apoptosis through the holo-Lcn2/Slc22a17/Fe³⁺ axis. This study provides insights into the application of BMSCs-based acellular therapies in islet transplantation.</p> Graphical Abstract <p></p>