Recent advances in molecular strategies and applications of heme sensors and probes

Abstract Heme, an iron-coordinated complex, is essential for organisms, serving vital functions when bound to hemoproteins. However, a subset of weakly or non-protein-bound heme, known as labile heme (LH), has emerged as a key molecule that mediates transcription and functions in cellular signaling. While recent studies have illuminated the regulatory system that governs the balance between the toxicity and benefits of heme, the subcellular dynamics of LH still remain largely enigmatic. This fundamental knowledge gap is due to the delay of the development of chemical tools essential for accurately monitoring intracellular LH fluctuations. This work comprehensively reviews the field, focusing on both genetically encoded heme sensors and small-molecule probes. We describe the detection mechanisms and cellular applications of these tools, highlighting their unique contributions to the field.