The study, led by Haibin Xia of Shaanxi Normal University in Xi’an and published in Cellular and Molecular Life Sciences, centers on a protein called FAM76B, short for family with sequence similarity 76 member B. Compared with famous immune molecules, FAM76B has been an obscure figure, its functions largely unmapped. The researchers suspected it might matter for macrophage behavior, and their experiments revealed something striking: when FAM76B was absent, macrophages could still engulf apoptotic cells normally, but they could not finish the job. The swallowed corpses piled up inside the cells, undigested. In other words, the defect was not in the eating but in the digesting, a selective failure in the post-phagocytic processing of apoptotic material.

That distinction matters enormously. Engulfment is only the first half of efferocytosis; the second half requires the macrophage’s internal degradation systems to break down the ingested cargo. The cell’s primary self-cleaning and cargo-disposal pathway is autophagy, a process in which cellular material is sequestered into membrane-bound vesicles and delivered to destructive enzymes. The team found that loss of FAM76B crippled autophagic activity in macrophages, leaving them unable to properly degrade the apoptotic cells they had taken in. Because undegraded cellular debris is a well-known trigger of anti-nuclear antibodies and other hallmarks of lupus, the finding immediately suggested a mechanistic bridge between a single protein and systemic autoimmunity.

To understand how FAM76B controls autophagy, the researchers delved into the world of RNA modifications, one of the hottest areas in molecular biology. Messenger RNA molecules carry chemical tags that influence their stability and translation, the most common being N6-methyladenosine, or m6A. This tag is read and interpreted by specialized m6A-binding proteins. One such reader is HNRNPA2B1, which the team discovered was being physically restrained by FAM76B. In the presence of FAM76B, HNRNPA2B1 stays out of the cytoplasm, away from its mRNA targets. But when FAM76B is missing, HNRNPA2B1 translocates into the cytoplasm, where it can bind m6A-modified transcripts and stabilize them.

One transcript in particular proved consequential: the mRNA encoding ISG15, an interferon-stimulated gene famous for its roles in antiviral defense and inflammation. With HNRNPA2B1 free to act, ISG15 mRNA was stabilized and ISG15 protein levels climbed. Here the story took another unexpected turn. ISG15 is best known for ISGylation, a process in which it is covalently attached to other proteins, modifying their behavior. Yet the researchers showed that the suppression of autophagy they observed was independent of ISGylation. Instead, ISG15 acted through a noncanonical mechanism: it physically interacted with HSPA8, a molecular chaperone, and disrupted HSPA8’s association with BECN1, also known as beclin 1, a core component of the autophagy-initiation machinery. Severing that partnership throttled the autophagic pathway at its source.

The team then moved from cells to living animals to test whether this molecular cascade mattered for disease. Using a pristane-induced model of lupus-like disease, they compared normal mice with mice lacking Fam76b. The deficient animals fared markedly worse, developing exacerbated disease characterized by defective clearance of apoptotic cells, elevated ISG15 expression, and reduced autophagy in their macrophages. The picture that emerged was coherent: without FAM76B, the m6A reader ran loose, ISG15 accumulated, autophagy stalled, dead-cell debris accumulated, and the immune system tipped toward autoimmunity.

Crucially, the researchers did not stop at demonstrating the damage. They tested whether intercepting the pathway could undo it. When they targeted ISG15 for inhibition in the disease setting, the intervention partially restored autophagic activity, improved the macrophages’ ability to process apoptotic cells, and alleviated disease manifestations in the mice. This therapeutic experiment elevates the finding from descriptive to actionable. It suggests that ISG15, or the molecular interactions it makes with HSPA8 and BECN1, could serve as a druggable node for treating lupus and potentially other conditions in which faulty efferocytosis fuels inflammation.

The study is notable for how many layers of cell biology it stitches together into a single regulatory axis. At the top sits FAM76B, a nuclear gatekeeper controlling where HNRNPA2B1 can operate. HNRNPA2B1, in turn, interprets m6A marks on RNA to determine the lifespan of specific transcripts, including ISG15. ISG15 then reaches into the autophagy machinery through a protein-protein interaction with the chaperone-mediated arm of the pathway. Each link in this chain, from RNA modification to chaperone sequestration to vesicle formation to debris clearance, represents an area of intense research interest in its own right, and the demonstration that they form a connected circuit in macrophages offers investigators a map of previously hidden connections.

For patients with systemic lupus erythematosus, the work offers a fresh explanation for a long-recognized puzzle. Defective clearance of apoptotic cells has been implicated in lupus for decades, and elevated type I interferon activity, the very signal that drives ISG15 expression, is a hallmark of the disease. What has been missing is a precise account of how these observations connect at the molecular level. By tracing a continuous pathway from an RNA-binding gatekeeper through a chaperone-disrupting interferon-stimulated protein to the autophagy engine, the Xi’an team has supplied a candidate answer, and one that comes with an obvious intervention point.

Caution is warranted, as it always is in translational science. The findings derive from cell culture experiments and a chemically induced mouse model, and lupus in humans is far more heterogeneous, involving multiple immune cell types, genetic risk factors, and environmental triggers. Whether FAM76B levels or ISG15 activity reliably track with disease in patients, and whether blocking ISG15’s interaction with HSPA8 is feasible and safe in people, remain open questions. ISG15 also performs beneficial antiviral functions, so any therapeutic strategy would need to navigate the balance between taming autoimmunity and preserving antiviral defense. Nevertheless, the identification of a FAM76B-HNRNPA2B1-ISG15-HSPA8 axis linking RNA modification to autophagy and efferocytosis gives lupus research a new set of molecular levers to pull, and it reminds us that sometimes the key to understanding a complex disease lies in a protein whose job, until now, nobody had bothered to read.

Subject of Research: The role of the FAM76B protein in regulating macrophage efferocytosis and systemic lupus erythematosus through an m6A-ISG15-autophagy axis

Article Title: FAM76B controls macrophage efferocytosis via m6A–ISG15–autophagy axis

Article References: Weng, G., Zhang, N., Wang, L., Liu, S., Zhao, W., Cheng, J., Yang, Y., Tang, Z., Zhao, J., Yang, P., Mao, Q., & Xia, H. (2026). FAM76B controls macrophage efferocytosis via m6A–ISG15–autophagy axis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06419-3

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06419-3

Keywords: FAM76B, efferocytosis, macrophages, autophagy, m6A, ISG15, HNRNPA2B1, HSPA8, systemic lupus erythematosus, RNA modification, apoptotic cell clearance, autoimmune disease