Abstract
Pulmonary fibrosis is a fatal interstitial lung disease marked by irreversible lung structure destruction. Understanding its molecular mechanisms is essential. Cold-inducible RNA-binding protein (CIRBP), a stress-responsive protein, stabilizes mRNA intracellularly and also acts extracellularly. We previously demonstrated that CIRBP is highly expressed in fibrotic lesions of idiopathic pulmonary fibrosis patients, with elevated serum levels correlating with disease progression and poor prognosis. However, its role in fibrosis remains unclear. We investigated CIRBP’s function using an in vivo bleomycin (BLM)-induced pulmonary fibrosis mouse model via intratracheal administration and an in vitro model with primary lung fibroblasts. CIRBP expression was markedly upregulated in the fibrotic regions of BLM-treated wild-type (WT) mice. CIRBP-deficient mice showed improved survival, reduced fibrosis, lower hydroxyproline content, and decreased expression of α-SMA and fibronectin. Therapeutic administration of C23, a CIRBP-derived inhibitory peptide, significantly suppressed fibrosis and improved survival in WT mice. In vitro, recombinant CIRBP promoted collagen secretion, fibroblast proliferation, and cell migration, which were inhibited by C23. Mechanistically, CIRBP-induced IL-6 production via TLR2 and TLR4, leading to fibroblast activation through autocrine signaling. These effects were suppressed by C23, TLR2/4 inhibitors, or IL-6 neutralization. Our findings identify CIRBP as a novel profibrotic factor and therapeutic target in pulmonary fibrosis.
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Data availability
The data that support the findings of this study are available from the corresponding authors upon reasonable request. The RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE294583 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294583). The data can be accessed with the following token: kfityyewrncrvir during peer review.
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Acknowledgements
The authors thank Enago (www.enago.jp) for the English language review. Part of this work was conducted at the Advanced Research Facilities & Services, Hamamatsu University School of Medicine. We sincerely thank Asuka Miyagi and Ryo Horiguchi for their invaluable assistance.
Funding
This study was supported by a grant from the Japan Society for the Promotion of Science (21K08176 to H.H.), a grant from the TERUMO LIFE SCIENCE FOUNDATION (22-III 4014 to H.H.), and a HUSM Grant-in-Aid. The funding source did not provide any input or contributions in the development of the research or manuscript.
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YM: Conception and design, data collection, data analysis and interpretation, manuscript writing. HH: Conception and design, data collection, data analysis and interpretation, manuscript writing, and final approval of the manuscript. AF, HW, HN, YI, HY, YS, MK, KF, NE, TF and NI: Data collection, data analysis, and supervision. TS: Conception and design, manuscript writing, and administrative support.
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Mochizuka, Y., Hozumi, H., Watanabe, H. et al. Cold inducible RNA binding protein promotes fibroblast activation and its inhibition represents a potential therapeutic target in pulmonary fibrosis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39649-3
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DOI: https://doi.org/10.1038/s41598-026-39649-3
