Hepatic immunopathogenesis of Crimean-Congo hemorrhagic fever virus: from acute liver injury to hypothesis-driven links with hepatocarcinogenesis

Crimean-Congo hemorrhagic fever virus (CCHFV) is a globally distributed, highconsequence zoonotic pathogen whose clinical spectrum extends far beyond hemorrhagic diathesis. Over recent years, mounting evidence has illuminated the central role of hepatic involvement in shaping both acute disease outcomes and potential postinfectious sequelae. The liver functions as a complex immunological organ, critically integrating viral replication dynamics with host innate and adaptive responses. This review synthesizes current knowledge on the hepatic immunopathogenesis of CCHFV, delineating the contributions of direct cytopathic effects and virusinduced inflammatory circuits orchestrated by hepatocytes, Kupffer cells, and liver sinusoidal endothelial cells. We further dissect how viral determinants, particularly genomic diversity within the nucleoprotein and other structural elements, modulate host sensing, immune evasion, and the intensity of liver injury. The potential for long-term hepatic consequences, including the hypothesis-driven risk of hepatocellular carcinoma (HCC), is examined through the lens of chronic inflammation, altered tissue remodeling, and emerging parallels with other viral hepatitides. Despite these advances, critical gaps persist in mapping cell-type-specific viral tropism, mechanistic genotype-phenotype correlations, and the interplay between acute hepatic injury and long-term liver health. We highlight future research priorities that include the application of single-cell and spatial omics, advanced humanized models, and integrated immunovirological surveillance, all poised to resolve outstanding questions and facilitate the rational design of vaccines and therapeutics that provide robust protection while averting immunopathological liver injury. Collectively, this review reframes CCHFV from an acute hemorrhagic threat to a major disruptor of hepatic immune homeostasis, underscoring the need for multidisciplinary approaches to mitigate both immediate and chronic consequences of infection.