Since its discovery in 1994, Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, has been identified as the causative agent of several malignancies, most notably Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease 1, 2, 3. KSHV belongs to the gammaherpesvirus family, which also includes Epstein–Barr virus (EBV) and Herpesvirus saimiri (HVS), and is characterized by its ability to establish life-long latency in host cells [4]. Once infected, KSHV persists in an episomal form and utilizes various viral proteins to manipulate host signaling pathways, thereby promoting cell survival and evading immune surveillance 5, 6•. Among the KSHV-encoded proteins, the K1 protein that encoded by the first open reading frame (ORF) of the viral genome is particularly notable, as the first ORFs of many gammaherpesviruses are known to encode proteins with oncogenic potential [7]. K1 is a transmembrane protein containing an immunoreceptor tyrosine-based activation motif (ITAM), which initiates signaling cascades upon phosphorylation [8]. Through interactions with SH2 domain-containing host proteins, K1 activates pathways such as NF-κB and phosphoinositide 3-kinase (PI3K)/Akt, leading to the promotion of angiogenesis, inhibition of apoptosis, and enhanced cellular transformation [9].

Notably, K1 is the most genetically variable region in the KSHV genome, leading to the classification of KSHV into genotypes A to F and the rare genotype Z [10]. These genotypes are not only geographically distinct but may also exhibit functional differences in terms of oncogenic potential and clinical presentation [11]. For instance, although genotype B is relatively rare, it exhibits a distinctive epidemiological pattern — being predominantly found in infants and children in sub-Saharan Africa 12, 13. Interestingly, recent studies have suggested a potential association between genotype B and better clinical prognosis, highlighting the need for further mechanistic investigations to elucidate the underlying biological basis of this observation [14]. Here, we discuss the current knowledge on the molecular functions of K1 and highlight the need to investigate how its sequence variability contributes to KSHV pathogenesis and disease heterogeneity.