Dendritic cells are crucial in the development of sepsis, yet the effect of ribophagy on dendritic cell activation remains unclear. This study aimed to investigate the potential role of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1), a selective autophagy receptor, on sequestering ribosomes in autophagosomes to maintain dendritic cell function during early stages of sepsis.

Splenic dendritic cells were isolated using CD11c⁺ microbeads and treated with lipopolysaccharide. Sepsis models were generated using cecal ligation and puncture. Expression of dendritic cell surface molecules was detected using flow cytometry. Cytokine level was quantified using enzyme-linked immunosorbent assay kits. Laser scanning confocal microscopy was employed to observe ribophagy and endoplasmic reticulum (ER) morphology. Transmission electron microscopy was used to examine autophagosomes containing ribosomes. Western blotting was performed to determine the levels of ribophagy- and ER stress-associated proteins.

The results showed that NUFIP1-mediated ribophagy was significantly activated under septic challenge and facilitated the functional activation of dendritic cells by mitigating excessive ER stress. Deletion of Nufip1 resulted in reduced expression of surface molecules on dendritic cells, inhibited T-cell proliferation, exacerbated peripheral immunosuppression and severe multiple organ damage, and increased mortality. Salubrinal, a specific inhibitor of EIF2A dephosphorylation, rescued dendritic cell dysfunction in septic mice with Nufip1 deficiency. Mechanistically, NUFIP1 interacted directly with ATF4 and regulated its nuclear translocation.

These findings suggest that NUFIP1 regulates ER stress through the EIF2AK3–ATF4–damage-inducible transcript 3 pathway, highlighting its critical regulatory role in sepsis. Thus, NUFIP1 represents a new target for sepsis therapy.