Suppression of reverse transcription of retroelements by lamivudine attenuates innate immunity and alleviates rheumatoid arthritis in mice.

Endogenous retroelements have emerged as important regulators of immune activation, and their reactivation can drive cGAS/STING signaling and downstream pro-inflammatory cytokine production. In rheumatoid arthritis (RA), macrophage-driven inflammation, osteoclast differentiation, and fibroblast-like synoviocyte (FLS) hyperproliferation collectively contribute to cartilage and bone destruction. Here, we investigated whether the nucleoside reverse transcriptase inhibitor lamivudine (3TC) could modulate endogenous retroelement activity and ameliorate arthritis progression. Using a collagen-induced arthritis (CIA) mouse model and in vitro systems with RANKL/M-CSF-induced RAW264.7 osteoclasts and primary FLS, we found that retroelements MERVL and Line1 were markedly upregulated in both joint tissues and osteoclasts, which was significantly suppressed by 3TC treatment. This inhibition was accompanied by downregulation of the cGAS/STING/NF-κB axis, reduced pro-inflammatory cytokine production, impaired osteoclast differentiation, and decreased FLS proliferation. Moreover, 3TC administration reduced joint inflammation and structural damage in CIA mice. In summary, our results indicate that 3TC mitigates RA pathology by blocking reverse transcription of endogenous retroelements and attenuating endogenous retroelement-driven innate immune signaling. Pharmacological inhibition of retroelements thus represents a promising therapeutic approach for RA.