ISGylation: is our genome yearning for such a modification?

• ISGylation is a reversible ubiquitin-like modification that regulates antiviral immunity, genomic stability, and tumorigenesis. • The enzymatic cascade (E1 UBA7, E2 UbcH8/UbcH6, E3 ligases) and deISGylation by USP18 are critical for ISG15 conjugation dynamics. • ISGylation crosstalks with ubiquitination and other PTMs, influencing protein fate and cellular stress responses. • Targeting ISGylation pathways offers therapeutic potential for genome instability-associated diseases and infections.