Retrotransposons, including LINE-1, SINEs, and human endogenous retroviruses (HERVs), are increasingly recognized as active regulators of genomic stability and immune signaling. This review examines their roles in genomic instability, innate immune activation, and chronic inflammation, with a focus on cGAS–STING and related pathways. It further explores their contributions to cancer, autoimmunity, fibrosis, and aging. We propose a unifying framework in which retrotransposons function as context-dependent integrators of cellular stress, linking genomic, immune, and metabolic dysfunction. Finally, we highlight key open questions and potential therapeutic strategies targeting retrotransposon activity. This work is shared as a preprint and has not undergone peer review.
Mohamed Esmat (Sat,) studied this question.