Bio: Hua Naranmandura is a Full Professor at Zhejiang University School of Medicine and the First Affiliated Hospital of Zhejiang University, and a core member of Zhejiang Province's leading leukemia research team. His research focuses on the molecular mechanisms of arsenic trioxide (ATO), the organelle-specific toxicity of its metabolites, and their application in APL treatment. He has published over 80 scientific papers in prestigious journals, including Cancer Discovery, Blood Cancer Discovery, Cell Reports, and Blood Cancer Journal, and serves as an editorial board member for Chemical Research in Toxicology, Toxicology and Applied Pharmacology, and Metallomics.

Abstract: Arsenic trioxide (ATO), traditionally recognized as an environmental pollutant, has emerged as a highly effective therapeutic agent for acute promyelocytic leukemia (APL) through its ability to induce PML-RARA degradation. Despite its clinical success, the precise molecular mechanisms underlying ATO's anticancer effects have remained elusive. In this study, we present a groundbreaking discovery by resolving the crystal structure of the PML B-box-2 domain, revealing that cysteine 213 forms a unique triad through B2 trimerization, which serves as the critical arsenic-binding site. This structural interaction triggers the subsequent degradation of PML-RARA, elucidating the molecular basis for ATO's therapeutic efficacy in APL. Our findings not only provide the first structural insights into arsenic's targeting of PML but also establish a foundation for the rational design of novel cancer therapeutics. This research bridges the gap between structural biology and clinical application, offering a paradigm for developing targeted therapies based on molecular interactions. The identification of this arsenic-binding triad represents a significant advancement in understanding ATO's mechanism of action and opens new avenues for drug discovery in oncology, potentially extending beyond APL to other malignancies.