Core Viewpoint - The study published in Science Translational Medicine highlights the role of the m6A demethylase FTO in the proliferation of age-associated B cells (ABC) and its connection to kidney damage in systemic lupus erythematosus (SLE), suggesting potential therapeutic targets [2][4][10]. Group 1: Mechanism of SLE and ABC Proliferation - The research identifies that the expansion of ABC in SLE is mediated by the m6A demethylase FTO, linking it to kidney damage [4]. - FTO is found to be highly expressed in ABC of SLE patients, with its expression positively correlated with immune damage in the kidneys [8]. - Overexpression of FTO in mouse and human B cells promotes ABC expansion and exacerbates SLE, while FTO deficiency improves autoimmune responses driven by ABC [9]. Group 2: TLR7-FTO-ATP6V1G1 Signaling Pathway - The study reveals that activation of the TLR7-MyD88 signaling pathway upregulates FTO expression, which in turn targets ATP6V1G1 in an m6A-dependent manner, promoting TLR7-driven ABC differentiation [9][10]. - FTO deficiency impairs lysosomal autophagy by reducing V-ATPase activity mediated by ATP6V1G1, leading to mitochondrial dysfunction in B cells [10]. - The accumulation of damaged mitochondria results in decreased oxidative phosphorylation and increased reactive oxygen species levels, inhibiting cell proliferation and ABC differentiation [10].