Ifih1, also known as the gene encoding melanoma differentiation-associated protein 5 (MDA5), is an essential innate immune regulator. It plays a crucial role in the early detection of viral infections, mediating the innate immune system's interferon response to double-stranded RNA (dsRNA) formed by certain viruses during their life cycle [3,4]. It is also involved in pathways related to inflammation and macrophage polarization.

In acute respiratory distress syndrome (ARDS), IFIH1 contributes to M1 macrophage polarization. Knockdown of IFIH1 in RAW264.7 cell line and BMDMs using shIFIH1 lentivirus confirmed that IFIH1 is a novel regulator for promoting M1 macrophage polarization, and it regulates M1 polarization by activating IRF3 [1]. In addition, in the context of HIV-1, loss-of-function screen in human monocyte-derived dendritic cells with short hairpin RNA-expressing lentivectors targeting IFIH1 prevented activation of the interferon-stimulated gene ISG15, demonstrating that IFIH1 is the innate immune receptor for intron-containing RNA from the HIV-1 provirus [2]. Loss-of-function variants of IFIH1 identified in nine patients through whole-exome sequencing were associated with recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C), and expression analysis in PBMCs of one patient with a specific variant showed disrupted immune response upon stimulation with Poly(I:C) [4].

In conclusion, Ifih1 is a key gene in the innate immune response, playing important roles in detecting viral infections and regulating macrophage polarization. Studies using gene-knockdown models in cell lines and identification of loss-of-function variants in patients have revealed its significance in diseases such as ARDS, HIV-1 infection-related inflammation, and SARS-CoV-2-related infectious diseases.