A first-in-class multimodal organomercury compound demonstrates preferential blast reduction with hematopoietic and immune restoration in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) remains a major therapeutic challenge due to non-specific cytotoxicity of conventional chemotherapeutics, leading to bone marrow suppression and immune dysfunction. Therapeutic strategies capable of simultaneously controlling leukemic blast and restoring hematopoietic activity, including immune composition remain limited. Here, we report seminal in vivo evaluation of a first-in-class intravenously deliverable organomercury- curcumin derivative, -Mercurin, in N-nitroso-N-ethylurea (ENU)-induced autochthonous ALL rat model with intact immune physiology. Previously, -Mercurin demonstrated selective leukemic cytotoxicity via reactive oxygen species (ROS)-mediated mitochondrial dysfunction and intrinsic apoptosis, in vitro and ex vivo. The preferential blast elimination and multimodal therapeutic profile is achieved by bonding mercury to the -carbon of curcumin, preserving its organic framework and biological properties, while conferring physiological stability along with aqueous solubility as sodium salt for intravenous delivery. Consequently, in present study -Mercurin significantly reduced circulating leukemic blasts and improved median survival compared to cytarabine. Longitudinal hematological analyses revealed progressive restoration of erythroid, myeloid and megakaryocytic compartments, along with sustained control of leucocytosis. Immunophenotypic profiling demonstrated coordinated immune restoration across peripheral blood, bone marrow, thymus, spleen, and lymph nodes. Histopathology indicated reduced leukemic infiltration with preserved tissue architecture. Biodistribution confirmed predominant renal clearance and no detectable accumulation in brain with substantially higher mercury retention in leukemia-bearing animals comparing to healthy treated controls. Mass-balance estimation indicated renal content is only [~]1.1% of total administered mercury. Collectively, -Mercurin demonstrated multimodal therapeutic activity by preferentially reducing leukemic burden, while restoring hematopoietic and immune function, highlighting its potential as a promising therapeutic candidate against ALL.