The Role of m6A Modification in the Development of Systemic Lupus Erythematosus via the TGF-β Signaling Pathway.

Abstract

N6-methyladenosine (m6A) modification is the most widespread RNA internal modification involved in RNA metabolism, participating in cell biology and immune responses. In the early stage of systemic lupus erythematosus (SLE), m6A modification can affect the production of autoantibodies by regulating the differentiation of T follicular helper (Tfh) cells and the generation of autoreactive B cells. With the development of SLE, its subsequent action in immune complexes (ICs)-deposited tissues is the promotion of excessive fibrosis, causing progressive organ damage. TGF-β is the central driver activating fibroblasts, inducing epithelial-to-mesenchymal transition (EMT), and promoting extensive extracellular matrix (ECM) deposition via the SMAD pathway, ultimately leading to tissue fibrosis and organ damage. m6A regulators can act on both upstream and downstream components of the TGF-β signaling pathway. They can synergize with TGF-β transcription factors to control the amplification of TGF-β signaling. Furthermore, they can work with target molecules downstream of the TGF-β receptor (TGF-βR) to tune TGF-β/SMAD pathway activity, increasing the expression of profibrotic transcripts. It is suggested that inhibition of m6A modification targeting the TGF-β signaling pathway can effectively reduce EMT and fibrosis in multiple organs, especially in the kidney, improving the long-term prognosis of SLE patients. In this review, we focus on the role of TGF-β in the pathogenesis of SLE, the mechanism by which m6A modifications affect the TGF-β signaling pathway, and its impact on EMT and fibrosis in different organs, trying to provide a new treatment strategy for the control of SLE symptoms.