CRLF1, or cytokine receptor-like factor 1, is a soluble type I cytokine receptor. Cytokines and their receptors are crucial in regulating immune function, inflammation, haematopoiesis, cell growth, and differentiation. CRLF1, upon interacting with its specific cytokine ligands, triggers intracellular signalling cascades, which can impact gene expression in target cells, thus influencing processes like cell proliferation, differentiation, or activation [1].

In cardiac fibrosis, CRLF1 is predominantly expressed in cardiac fibroblasts. Its expression is up-regulated in fibrotic models. Gain-and loss-of-function experiments in neonatal mice cardiac fibroblasts showed that CRLF1 overexpression promotes fibrosis, while silencing has the opposite effect, with CRLF1 acting via the ERK1/2 signalling pathway [2].

In ovarian cancer, CRLF1 is part of mTORC2, enhancing AKT Ser473 phosphorylation through SIN1, inhibiting pyroptosis, and conferring chemoresistance. Binding-defective CRLF1 variants can reverse this, promoting pyroptosis and chemosensitization [3].

In the ligamentum flavum hypertrophy, CRLF1 is up-regulated. TGF-β1 increases its mRNA expression through the SMAD3 pathway, and CRLF1 enhances fibrosis via the ERK pathway. Knockdown of CRLF1 reduces fibrosis [4].

In papillary thyroid carcinoma, CRLF1 promotes proliferation and metastasis. It binds MYH9 to enhance its own stability, activates the ERK pathway, and up-regulates ETV4, which is associated with poor prognosis [5]. Also, CRLF1 promotes the malignant phenotypes of papillary thyroid carcinoma by activating the MAPK/ERK and PI3K/AKT pathways [8].

In osteochondral repair, BMSCs overexpressing CRLF1 improve osteochondral defect repair. A homodimeric CRLF1 complex released by BMSCs enhances repair via inhibiting catabolic events in chondrocytes and stimulating chondrogenic differentiation of precursor cells [6].

In intervertebral disc degeneration, the CRLF1/CLCF1 heterodimer activates JAK/STAT3 signalling, accelerating nucleus pulposus cell senescence. Targeting CRLF1 reduces extracellular matrix degradation and alleviates cell senescence [7].

Mutations in CRLF1 can cause familial achalasia and are also associated with Crisponi or cold-induced sweating syndrome type 1 [9].

In conclusion, CRLF1 plays diverse and significant roles in various biological processes and disease conditions. Through gene knockout or conditional knockout models in mice and other loss-of-function experiments, its functions in cardiac fibrosis, cancer, ligamentum flavum hypertrophy, osteochondral repair, and intervertebral disc degeneration have been revealed. These findings provide potential therapeutic targets for related diseases.