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NmrA-like proteins are NAD(P) (H) interacting molecules whose structures are similar to that of short-chain dehydrogenases. In this review, we focus on an NADP(H) sensor, HSCARG (also named NMRAL1), which is a NmrA-like protein that is widely present in mammals, and provide a comprehensive overview of the current knowledge of its structure and physiological functions. HSCARG selectively binds to the reduced form of type II coenzyme NADPH via its Rossmann fold domain. In response to reduction of intracellular NADPH concentration, HSCARG transforms from homodimer to monomer and exhibits enhanced interactions with its binding partners. In the cytoplasm, HSCARG negatively regulates innate immunity through impairing the activities of NF- κ B and RLR pathways. Besides, HSCARG regulates redox homeostasis via suppression of ROS and NO generation. Intensive and persistent oxidative stress leads to translocation of HSCARG from the cytoplasm to the nucleus, where it regulates the DNA damage response. Taken together, HSCARG functions as a linkage between cellular redox status and other signaling pathways and fine-tunes cellular response to redox changes.