Proteomics of heterogeneous megakaryocytes identifies JI051 as an enhancer of platelet biogenesis.

Induced pluripotent stem cell-derived immortalized megakaryocyte cell lines (imMKCLs) exhibit substantial heterogeneity, which poses a major barrier to efficient ex vivo production of platelet-like particles (PLPs). In this study, we combined proteomic profiling with principal component analysis to uncover regulatory factors influencing imMKCL maturation. Through correlation-based omics screening, prohibitin 2 (PHB2) was identified as a putative inhibitory node, and JI051, a small molecule previously reported to bind PHB2, was found to enhance PLP production. JI051 accelerated proplatelet-like extensions and increased PLP yield without affecting basic functional markers. Transcriptomic analysis showed that JI051 induced transcriptional changes consistent with megakaryocyte maturation and PLP biogenesis. Together, these findings identify JI051 as an enhancer of platelet biogenesis and provide a strategy to mitigate cellular heterogeneity in imMKCL megakaryocytes for scalable artificial platelet production, with potential benefits for emergency blood supply and cost-effective bioproduction.