Unraveling the Therapeutic Landscape of miRNAs in Kaposi Sarcoma

Kaposi sarcoma (KS) is a vascular malignancy caused by human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV). Clinically, KS presents with characteristic lesions on the skin or mucosal surfaces and may extend to internal organs, leading to serious complications such as gastrointestinal bleeding and lymphedema. The prevalence of KSHV varies markedly by geography, with the highest rates reported in sub-Saharan Africa, the Mediterranean region, and high-risk populations such as individuals living with HIV/AIDS. KS pathogenesis is primarily driven by KSHV-induced cellular transformation, persistent inflammation, and angiogenesis, regulated by viral proteins and microRNAs (miRNAs). miRNAs, as key post-transcriptional gene regulators, play dual roles in cancer progression, acting as either oncogenes (oncomiRs) or tumor suppressors. In KS, oncogenic miRNAs such as KSHV-encoded miR-K12-11 and miR-K12-1 promote tumorigenesis by inhibiting tumor-suppressor pathways and activating signaling cascades, including NF-κB/IL-6/STAT3. Conversely, tumor-suppressor miRNAs such as miR-34a, Let-7, and miR-126 are often downregulated, enabling uncontrolled cell proliferation, angiogenesis, and immune evasion. Emerging miRNA-based therapeutic strategies show preclinical promise for KS management, particularly by restoring tumor-suppressive miRNAs or targeting oncomiRs. The development of nanoparticle delivery systems addresses critical limitations such as miRNA instability and ensures targeted delivery, representing a significant advance in therapeutic design. This review examines the multifaceted role of miRNAs in KS pathogenesis and explores innovative miRNA-based therapeutic interventions to combat this malignancy effectively.