NUFIP1 gain of function promotes fibrotic remodeling and reveals a ZNHIT3-linked metabolic vulnerability in idiopathic pulmonary fibrosis models.

BACKGROUND: Fibroblast activation and extracellular matrix deposition are central features of IPF, but the molecular programs that sustain pathogenic fibroblast states remain incompletely defined. NUFIP1 has been implicated in ribonucleoprotein biology and cellular stress responses, yet its role in pulmonary fibrosis is unknown. METHODS: NUFIP1 expression was examined in lung tissues from patients with IPF, bleomycin-induced pulmonary fibrosis in mice, and TGF-β1-stimulated human lung fibroblasts. Gain-of-function studies were performed in MRC-5 fibroblasts and in mice using AAV-mediated NUFIP1 overexpression. The association between NUFIP1 and ZNHIT3 was assessed by co-immunoprecipitation and surface plasmon resonance. The effect of CB-839 on NUFIP1-ZNHIT3 interaction, fibroblast activation, and pulmonary fibrosis was evaluated in vitro and in vivo. Public bulk and single-cell RNA-seq datasets were analyzed to assess the clinical relevance of NUFIP1 expression in human IPF. RESULTS: NUFIP1 expression was increased in IPF lung tissue and showed spatial overlap with Vimentin-positive fibrotic regions. AAV-mediated NUFIP1 gain of function was sufficient to induce fibrotic remodeling relative to vector controls, with a magnitude comparable to a separate bleomycin reference group. NUFIP1 associated with ZNHIT3, and CB-839 altered the apparent association under the tested conditions while reducing NUFIP1-associated fibrotic readouts. Public transcriptomic analyses supported a modest donor-level increase in whole-lung NUFIP1 expression and detected NUFIP1 across multiple lineages, including IPF-associated fibroblast states. CONCLUSIONS: These gain-of-function data support a profibrotic effect of increased NUFIP1 in experimental models. ZNHIT3 is a candidate binding partner, and CB-839 reduced NUFIP1-associated fibrotic readouts at the tested dose. Pathway specificity, endogenous necessity, and clinical relevance remain to be established.