FAM76B controls macrophage efferocytosis via m6A–ISG15–autophagy axis

Efficient clearance of apoptotic cells by macrophages (efferocytosis) is essential for maintaining immune homeostasis, and its disruption contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here, we identify FAM76B as a key regulator of macrophage-mediated apoptotic cell clearance through modulation of autophagy. Loss of FAM76B impaired degradation of engulfed apoptotic cells without affecting phagocytic uptake, indicating a selective defect in post-phagocytic processing. Mechanistically, FAM76B restricts cytoplasmic translocation of the m 6 A reader HNRNPA2B1, thereby limiting m 6 A-dependent stabilization of ISG15 mRNA. Fam76b deficiency leads to increased ISG15 expression, which suppresses autophagy via a noncanonical, ISGylation-independent mechanism. Specifically, ISG15 interacts with HSPA8 and disrupts its association with BECN1, resulting in impaired autophagic activity. In vivo, Fam76b deficiency exacerbates pristane-induced lupus-like disease, characterized by defective apoptotic cell clearance, elevated ISG15 expression, and reduced autophagy. Targeted inhibition of ISG15 partially restores autophagy, improves efferocytosis, and alleviates disease manifestations. Collectively, these findings define a FAM76B–HNRNPA2B1–ISG15–HSPA8 regulatory axis linking RNA modification to autophagy and efferocytosis, thereby providing mechanistic insight into immune homeostasis and lupus pathogenesis.