Emerging viroporins, RBP dynamics, and skeletal remodeling: Targeting liquid-liquid phase separation for dual...

Emerging and re-emerging viral pathogens, particularly Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Chikungunya virus (CHIKV), are currently recognized as a significant global public health issue, commonly leading to devastating persistent complications including inflammatory bone disorders and long-lasting arthralgia. Although systemic cytokine storm has been reported as a significant factor, the particular intracellular processes through which these viruses affect bone homeostasis are still poorly understood. Recent studies underscore Liquid-Liquid Phase Separation (LLPS) and RNA-Binding Proteins (RBPs) as significant regulatory mechanisms manipulated by these viruses. Particularly, the SARS-CoV-2 Nucleocapsid protein exploits its intrinsically disordered regions to promote LLPS, facilitating viral assembly by the active inhibition of a key host anti-viral mechanism, known as host Stress Granules. Studies suggest that this biophysical interaction can affect the stability of the HuR RBD, impairing the nuclear β-catenin localization and then Wnt-mediated osteogenesis. Despite increasing recognition of post-viral musculoskeletal complications, the mechanistic links between viral persistence, host RBP dysfunction, and impaired bone remodeling remain poorly defined. This review incorporates viral LLPS, stress granule impairment, and osteogenic signaling into a unified 'Two-Hit' pathogenic framework. It also addresses key knowledge gaps, including the lack of longitudinal clinical validation and in vivo evidence associating LLPS impairment to skeletal disorders. Interestingly, this framework represents translational opportunities for dual-action therapeutic strategies that simultaneously impair viral condensates and recover host RBP-associated osteogenic signaling. Targeting the virus-host phase interface can introduce a potential approach not only for antiviral therapies but also for inhibiting post-viral musculoskeletal complications.